NZ755866A - Anti-fibrotic compounds - Google Patents

Anti-fibrotic compounds

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Publication number
NZ755866A
NZ755866A NZ755866A NZ75586618A NZ755866A NZ 755866 A NZ755866 A NZ 755866A NZ 755866 A NZ755866 A NZ 755866A NZ 75586618 A NZ75586618 A NZ 75586618A NZ 755866 A NZ755866 A NZ 755866A
Authority
NZ
New Zealand
Prior art keywords
phenyl
methoxy
acrylamido
benzoic acid
propynyloxy
Prior art date
Application number
NZ755866A
Other versions
NZ755866B2 (en
Inventor
Thomas Miller
Nikolaos Papaioannou
Original Assignee
Certa Therapeutics Pty Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Certa Therapeutics Pty Ltd filed Critical Certa Therapeutics Pty Ltd
Publication of NZ755866A publication Critical patent/NZ755866A/en
Publication of NZ755866B2 publication Critical patent/NZ755866B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/20—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton containing six-membered aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
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    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/72—Nitrogen atoms
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    • C07D215/20—Oxygen atoms
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Abstract

Provided herein are anti-fibrotic compounds, in particular those of Formula (I), that inhibit the TGF-beta signaling pathway. Also provided are pharmaceutical compositions comprising the anti-fibrotic compounds, and methods of treating diseases or conditions associated with fibrosis, inflammation, and benign or malignant neoplastic diseases in a subject by administering a compound or composition described herein. (Formula (I))

Description

ANTI-FIBROTIC COMPOUNDS Cross-Reference to Related Applications The present application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application Serial No. 62/454,358, filed February 3, 2017. The ty of which is incorporated herein by nce.
Field of the Invention The present invention relates generally to nds that inhibit fibrosis, and use of the compounds in the treatment of l disorders, in particular conditions associated with tissue fibrosis. ound of the Invention Tranilast (n-[3,4-dimethoxycinnamoyl] anthranilic acid) is an anti-fibrotic agent approved in Japan for the treatment of ic skin disorders such as keloids and scleroderma.
Although the precise mechanisms and mode of action are not tely understood, its ability to inhibit ERK phosphorylation, a major intermediate in the TGF-P signalling pathway, may underlie its antifibrotic effects, with known actions of ast including the inhibition of TGFP-induced extracellular matrix production in a range of cell types. Tranilast has also been shown to attenuate TGF-P-induced en synthesis in cardiac fibroblasts using an experimental model of diabetic cardiac disease.
Fibrosis is a common response to a range of tissue insults that may lead to organ dysfunction. Diseases that are characterized by such pathological fibrosis include hepatic cirrhosis, pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischaemic and nonischaemic ), diabetic pathy, scleroderma, excessive scar tissue post surgery or device insertion, progressive kidney disease, glomerulonephritis, hypertension, heart failure due to ischaemic heart disease, ar heart disease or hypertensive heart disease and hypertrophic scars. In addition, the elaboration of pathological matrix also has a role in fibroproliferative tumor progression and metastasis.
Diabetic subjects have a two- to old increase risk of developing heart e. In addition to ischaemic heart disease, heart failure in diabetes is also associated with a cardiomyopathy, independent of coronary artery e. This so-called tic cardiomyopathy" is characterised histologically by myocardial fibrosis with reduced myocardial elasticity, impaired contractility and overt c dysfunction. Accordingly, strategies that reduce the pathological accumulation of extracellular matrix have been advocated as potential therapies for the treatment and prevention of heart failure in both diabetic and nondiabetic states.
Current treatment of chronic heart e focuses on the tion of the neurohormonal activation that lly develops in response to the ng functional abnormalities. However, despite such therapy, frequently used in combination, cardiac dysfunction continues to progress in the majority of patients. Given the importance of ogical fibrosis in adverse cardiac remodelling, a potential role of antifibrotic agents has been suggested. Studies conducted over more than a decade have consistently ted a major role for the prosclerotic growth factor, transforming growth factor-P (TGF-P) in organ fibrosis and dysfunction, such that blockade of its expression and action represent an important therapeutic target.
Tranilast has also been shown to reduce inflammation in allergic diseases, such as allergic rhinitis and bronchial asthma, etc., and have anti-proliferative activity.
However, it has recently been shown that genetic factors in certain ts, specifically a Gilbert’s me UGT1A1 variant, confers susceptibility to tranilast-induced hyperbilirubinemia. Such hyperbilirubinemia may be associated with tranilast itself or the formation, in vivo, of the ing tranilast metabolite, An ongoing need exists to identify and provide drugs with potential anti-fibrotic, anti­ inflammatory, and roliferative or eoplastic activity for the treatment or prevention of diseases associated with fibrosis, diseases characterized by inflammation and neoplastic disease (both benign and malignant), and as alternatives/adjuncts to tranilast.
Summary of the Invention In one aspect, provided are compounds of Formula I: Z-r3 <1 (R6)m r2-y> or pharmaceutically acceptable salts, co-crystals, ers, stereoisomers, solvates, hydrates, polymorphs, isotopically enriched derivatives, or prodrugs thereof, wherein: Tis AYK, X is O, NR10, -NR10C(O)-, or a bond; Y is O, NR10, -C(0)NR10 or a bond; Z is O, NR10, or a bond; R and R are independently hydrogen, alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, lkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R1 2 are each optionally substituted with 1-3 independent substituents R ;o or R and R together with the atoms to which they are attached form a heterocyclyl ring;1 2 R is hydrogen, heteroalkyl, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,o heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is ally substituted with 1-3a independent substituents R ;o R4 and R5 are hydrogen; each occurrence of R6 is, independently, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, alkoxy, aryl, aryl, heterocyclyl, NRaRb, or -S(0)2RC; G is C(0)R7 or hydrogen; R7is OH or NHR9; m is 0, 1, or 2; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, yl, oxo, o aryl, aryl, heterocyclyl, , -S(0)2RC, or -C02Rd; R9is heteroaryl, heterocyclyl, or -S(0)2RC, wherein R9is optionally substituted with 1-3 independent substituents R ;o R is hydrogen or alkyl optionally substituted with 1-3 independent substituents R ; and10 8 each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cyclylalkyl, aryl, aryl, heterocyclyl, C(0)0Ci-6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are ed form a heterocyclyl ring; provided that when G is hydrogen, then m is not 0; provided that when G is C(0)R7, R7 is OH, and -Z-R3 is H, then at least one of -X-R1 and-Y-R is-O-heterocyclyl or heterocyclyl, or R and R together with the atoms to which they are attached form a heterocyclyl ring; provided that when-X-R is H, then neither-Y-R nor-Z-R are hydrogen;1 2 3 provided that when-Y-R is H, then neither-X-R nor-Z-R are hydrogen; and2 13 provided that when-Z-R is H, then neither-X-R nor-Y-R are hydrogen.
Exemplary compounds of Formula I include, but are not limited to: (E)-N-(2-fluorophenyl)(3-methoxy(propyn-1 -yloxy)phenyl)acrylamide (1); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-lH-l,2,4-triazol yl)phenyl)acrylamide (2); (E)-N-(2-chlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (3); (E)-N-(2-bromophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (4); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(o-tolyl)acrylamide (5); (2-cyanophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (6); (E)-N-(3,4-dichlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (7); (2-(2H-tetrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (16); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (17); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,2,4-oxadiazol yl)phenyl)-acrylamide (18); (3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3 -yl)phenyl)acrylamide (19); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (20); (E)-N-(2-(l,3,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (21); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-pyrazol yl)phenyl)-acrylamide (22); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)acryl-amide (23); (E)-N-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (24); (E)-N-(2-(lH-imidazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (25); (3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-imidazol yl)phenyl)acrylamide (26); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N- (methylsulfonyl)benzamide (27); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)phenyl)acryl-amide (28); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,3,4-oxadiazol nyl)-acrylamide (29); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2H-tetrazol yl)benzamide (31); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methylpiperidin yl)benzamide (36); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(oxetan yl)benzamide (38); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (44); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 4-yl)benzamide (47); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 3-yl)benzamide (48); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(piperidin yl)benzamide (49); (3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid (51); (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76); -(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamide (77); (E)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)-benzoic acid (78); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79); 2-[[(E)(3-methoxypropynoxypyrrolidinyloxyphenyl)prop enoyl]amino]benzoic acid (80); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylpyrrolidinyl)oxypropynoxyphenyl ]propenamide (81); (E)-N-(2-cyanophenyl)(3-methoxypropynoxypyrrolidinyloxy-phenyl)prop- 2-enamide (82); 2-[[(E)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (83); 2-[[(E)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (84); (E)-N-(2-cyanophenyl)[3-methoxy(2-morpholinoethoxy)propynoxyphenyl ]propenamide (85); 2-[[(E)[2-[3-(dimethylamino)propoxy]methoxypropynoxy-phenyl]prop enoyl]amino]benzoic acid (86); (E)-N-(2-cyanophenyl)[2-[3-(dimethylamino)propoxy]methoxypropynoxyphenyl ]propenamide (87); (E)-N-(2-cyanophenyl)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enamide (88); WO 44620 (E)-N-(2-cyanophenyl)[3-methoxy[(l-methylpiperidyl)oxy]propynoxyphenyl ]propenamide (89); 2-[[(E)[4-(cyclopropylmethoxy)[2-(dimethylamino)ethoxy]methoxyphenyl ]propenoyl]amino]benzoic acid (90); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (91); (E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (92); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (93); (E)-N-(2-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxy-phenyl]prop enamide (94); (E)(3-(3,4-dimethoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (95); (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96); (E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid (97); (E)(3-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (98); (E)(3-(3-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (99); (3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101); (E)(3-(3-methoxymorpholinophenyl)acrylamido)benzoic acid (103); (E)(3-(4-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (104); 2-[[(E)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (108); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (HO); WO 44620 (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (ill); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (112); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)-acrylamide (114); (E)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116); (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamido)benzoic acid (117); (E)-N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (120); N-(4-cyanophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121); 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane- 1-carboxamide (122); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-fluorophenyl)acrylamide (123); (E)-A/-(4-cyanophcnyl)(3-cthyl(propyn-l -yloxy)phcnyl)acrylamidc (124); (3-ethyl(propyn-l-yloxy)phenyl)-N-(4-fluorophenyl)acrylamide (125); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(2- fluorophenyl)acrylamide (127); (2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4- fluorophenyl)acrylamide (128); (E)-N-(4-cyanophenyl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamide (129); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (130); (E)-N-(4-cyanophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (131); (E)-N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (132); WO 44620 N-(4-fluorophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (133); N-(4-cyanophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (135); N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (136); N-(4-cyanophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (137); N-(2-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (138); (4-cyanophenyl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (139); (E)(3-methoxy( 1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 - yl)phenyl) acrylamide (140); (E)-N-(2-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (141); N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (143); 2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 -yl)phenyl)cyclopropanecarboxamide (144); luorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (145); (E)-N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147); N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (148); N-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (149); (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151); (E)-N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (152); (E)-N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (153); N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (154); N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (155); N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (156); N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (157); 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(3- (methylsulfonyl)phenyl) cyclopropanecarboxamide (158); (E)-N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol hoxy)phenyl)acrylamide (159); (E)-N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylamide (160); and pharmaceutically acceptable salts thereof.
In another aspect, provided are the following compounds: (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-phenylacrylamide (8); methyl (E)-l-(3-(3-methoxy(propyn-l-yloxy)phenyl)acryloyl)-l,2,3,4- tetrahydroquinolinecarboxylate (9) (3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop- 2-en-l-one (10); (E)-l-(3,4-dihydroquinoxalin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (11); (E)-l-(2,3-dihydro-4H-benzo[b][l,4]oxazinyl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (12); (E)-N-((trans)aminocyclohexyl)(3-methoxy(propyn-lyloxy l)acrylamide (13); (E)-l-(4-hydroxy-3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (14); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop en-l-one (15); (E)-N-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn lyloxy) phenyl) acrylamido) benzamide (30); (E)-N-(3-(dimethylamino)propyl)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido) benzamide (32); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2- methoxyethyl)benzamide (33); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(4-methylpiperazinl-yl )ethyl)benzamide (34); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-morpholino benzamide (35); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methylpiperidin hyl)benzamide (37); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((tetrahydrofuran yl)methyl)benzamide (39); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methyl-lH- imidazolyl)methyl)benzamide (40); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (41); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (42); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (43); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (45); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (46); (E)(3-(3-methoxy(piperidinylmethoxy)phenyl)acrylamido)benzoic acid (50); (E)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid (52); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (53); (3-(3-methoxy(oxetanylmethoxy)phenyl)acrylamido)benzoic acid (54); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (55); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (56); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (57); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (58); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (59); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (60); (E)(3-(4-methoxy(2-methoxyethoxy)phenyl)acrylamido)benzoic acid (61); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (62); (E)(3-(4-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (63); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (64); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (65); (E)(3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (67); (E)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); (E)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic acid (70) (E)(3-(4-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (71); (E)(3-(3-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (72); (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73); (E)(3-(4-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (74); (E)(3-(3-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (75); (E)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100); 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102); (E)(3-(3-ethylmethoxyphenyl)acrylamido)benzoic acid (105); (E)(3-(3-(cyclopropylmethyl)methoxyphenyl)acrylamido)benzoic acid (106); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)prop- 2-en-l-one (113); (E)-1 -(2H-benzo[b] [ 1,4]oxazin-4(3H)-yl)-3 -(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propen-1 -one (115); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)propen-1 -one (118); (2H-benzo[b] [ 1,4]oxazin-4(3H)-yl)(2-(3-methoxy(propyn-1 -yloxy) phenyl) cyclopropyl) methanone (119); (E)(3-ethyl(propyn-l-yloxy)phenyl)-l-(3-hydroxy-lH-indazol-l-yl)propen-l- one (126); (3-hydroxy- IH-indazol- l-yl)(2-(3-methoxy(propyn- l-yloxy)phenyl)cyclopropyl) methanone (134); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)propen-l-one (142); (3-hydroxy-lH-indazol-l-yl)(2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl) cyclopropyl)methanone (146); (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide (150); and pharmaceutically able salts thereof.
In another aspect, ed are pharmaceutical compositions comprising any compound of the t disclosure (e.g., compound of a I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
In another aspect, provided are methods of disease or condition associated with fibrosis in a t in need thereof, the method comprising stering any compound of the present disclosure {e.g., nd of Formula I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid)) or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition sing any compound of the present disclosure (e.g.. compound of a I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid)) or pharmaceutically acceptable salt thereof, to the subject. In certain embodiments, the disease or condition associated with fibrosis is selected from the group consisting of ic skin disorders, lung e, heart disease, kidney disease, and cirrhosis of the liver. In certain embodiments, the the disease or condition associated with is is kidney disease. In certain embodiments, the kidney disease is progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative ulonephritis, diffuse erative glomerulonephritis, nous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy. In certain embodiments, the disease or condition associated with fibrosis is focal segmental glomerulosclerosis.
In another aspect, provided are kits comprising any nd of the t disclosure (e.g., nd of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid)) or a pharmaceutically acceptable salt f, or a pharmaceutical composition comprising any compound of the present disclosure (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid)) or pharmaceutically acceptable salt thereof. In certain embodiments, the kits further se instructions for administration (e.g., human administration).
The details of certain embodiments of the invention are set forth in the Detailed Description of Certain Embodiments, as described below. Other features, objects, and advantages of the invention will be apparent from the Definitions, Examples, Figures, and Claims.
Brief Description of the Drawings Figure 1 shows a pharmacokinetic profile plot (plasma concentration vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 116 to male SD rats.
Figure 2 shows shows a pharmacokinetic profile plot (plasma concentration vs. time) after daily administration (5 days) of 75 mg/kg, and 350 mg/kg of 116 to male SD rats.
Figure 3 shows a pharmacokinetic profile plot (% IC50 coverage vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 116 to male SD rats in comparison to known values of a known compound, (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid.
Figure 4 shows a pharmacokinetic profile plot (plasma concentration vs. time) after stration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 107 to male SD rats.
Figure 5 shows shows a pharmacokinetic profile plot (plasma concentration vs. time) after daily administration (5 days) of 75 mg/kg, and 350 mg/kg of 107 to male SD rats.
Figure 6 shows a pharmacokinetic profile plot (% IC50 coverage vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 107 to male SD rats in comparison to known values of a known nd, (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid.
Figure 7 shows a pharmacokinetic profile plot (plasma concentration vs. time) after stration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 102 to male SD rats.
Figure 8 shows shows a pharmacokinetic profile plot (plasma concentration vs. time) after daily administration (5 days) of 75 mg/kg, and 350 mg/kg of 102 to male SD rats.
Figure 9 shows a pharmacokinetic profile plot (% IC50 coverage vs. time) after administration of 2 mg/kg, 20 mg/kg, 75 mg/kg, and 350 mg/kg of 102 to male SD rats in comparison to known values of a known compound, (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid.
Definitions Chemical definitions Definitions of specific onal groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed., inside cover, and ic functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are bed in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic ormations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 n, Cambridge University rd Press, Cambridge, 1987.
Compounds described herein can comprise one or more asymmetric s, and thus can exist in various stereoisomeric forms, e.g., enantiomers and/or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al. Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et ah. Tetrahedron 33:2725 ; Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H., Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The invention additionally encompasses compounds as individual isomers ntially free of other isomers, and alternatively, as es of various isomers.
In a formula, JVW is a single bond where the chemistry of the moieties immediately attached thereto is not specified, — is absent or a single bond, and = or is a single or double bond.
Unless otherwise stated, ures depicted herein are also meant to include nds that differ only in the ce of one or more isotopically enriched atoms. For e, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, ement of F with F, or the replacement of C with C or C are within the scope of the disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays.
When a range of values is listed, it is intended to encompass each value and sub-range within the range. For example "Ci_6 alkyl" is intended to encompass, Ci, C2, C3, C4, C5, Q,, C\-e, C1-5, Ci_4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and Cs_6 alkyl.
The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and carbocyclic groups. Likewise, the term "heteroaliphatic" refers to heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic groups.
The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 10 carbon atoms ("Ci-io alkyl"). In some embodiments, an alkyl group has 1 to 9 carbon atoms ("C1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8 carbon atoms ("Ci-g alkyl"). In some embodiments, an alkyl group has 1 to 7 carbon atoms ("C1-7 alkyl"). In some embodiments, an alkyl group has 1 to 6 carbon atoms ("Ci_6 alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon atoms ("C1-5 alkyl"). In some ments, an alkyl group has 1 to 4 carbon atoms ("Ci_4 alkyl"). In some embodiments, an alkyl group has 1 to 3 carbon atoms ("C1-3 alkyl"). In some embodiments, an alkyl group has 1 to 2 carbon atoms ("C1-2 alkyl"). In some embodiments, an alkyl group has 1 carbon atom ("Ci alkyl"). In some embodiments, an alkyl group has 2 to 6 carbon atoms ("C2-6 alkyl"). Examples of Ci_6 alkyl groups include methyl (Ci), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., nbutyl , tert-butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentanyl, amyl, neopentyl, 3- methylbutanyl, tertiary amyl), and hexyl (Ce) (e.g., n-hexyl). Additional examples of alkyl groups include yl (C7), n-octyl (Cg), and the like. Unless otherwise specified, each instance of an alkyl group is independently unsubstituted (an "unsubstituted alkyl") or substituted (a "substituted alkyl") with one or more substituents (e.g., halogen, such as F). In certain embodiments, the alkyl group is an unsubstituted C1-10 alkyl (such as unsubstituted Ci_6 alkyl, e.g., -CH3 (Me), unsubstituted ethyl (Ft), unsubstituted propyl (Pr, e.g., unsubstituted n-propyl (n-Pr), unsubstituted isopropyl (i-Pr)), unsubstituted butyl (Bu, e.g., unsubstituted l (n-Bu), unsubstituted utyl (tert-Bu or t-Bu), unsubstituted sec-butyl (sec-Bu), unsubstituted yl (i-Bu)). In certain embodiments, the alkyl group is a substituted C1-10 alkyl (such as tuted C1-6 alkyl, e.g., -CF3, Bn).
The term "haloalkyl" is a substituted alkyl group, wherein one or more of the hydrogen atoms are independently replaced by a halogen, e.g., fluoro, bromo, chloro, or iodo. In some ments, the haloalkyl moiety has 1 to 8 carbon atoms ("Ci_g haloalkyl"). In some ments, the haloalkyl moiety has 1 to 6 carbon atoms ("Ci_6 kyl"). In some embodiments, the haloalkyl moiety has 1 to 4 carbon atoms ("Ci_4 kyl"). In some embodiments, the haloalkyl moiety has 1 to 3 carbon atoms ("C1-3 kyl"). In some embodiments, the haloalkyl moiety has 1 to 2 carbon atoms ("C1-2 haloalkyl"). Examples of kyl groups include -CHF2, -CH2F, -CF3, -CH2CF3, -CF2CF3, -CF2CF2CF3, -CC13, -CFCI2, -CF2C1, and the like.
The term "heteroalkyl" refers to an alkyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, en, or sulfur within (i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkyl group refers to a saturated group having from 1 to 20 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-20 alkyl"). In some embodiments, a heteroalkyl group is a ted group having 1 to 18 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-ig alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 16 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_i6 alkyl"). In some embodiments, a alkyl group is a saturated group having 1 to 14 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi_i4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 12 carbon atoms and 1 or more atoms within the parent chain ("heteroCi-12 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi-10 alkyl"). In some ments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1 or more heteroatoms within the parent chain ("heteroCi.g alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 6 carbon atoms and 1 or more atoms within the parent chain roCi-6 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain ("heteroCi_4 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom within the parent chain ("heteroCi-3 alkyl"). In some embodiments, a heteroalkyl group is a ted group having 1 to 2 carbon atoms and 1 heteroatom within the parent chain ("heteroCi_2 alkyl"). In some embodiments, a heteroalkyl group is a saturated group having 1 carbon atom and 1 atom ("heteroCi alkyl"). In some embodiments, the heteroalkyl group defined herein is a partially unsaturated group having 1 or more heteroatoms within the parent chain and at least one unsaturated carbon, such as a carbonyl group. For example, a heteroalkyl group may comprise an amide or ester functionality in its parent chain such that one or more carbon atoms are unsaturated carbonyl groups. Unless otherwise specified, each instance of a heteroalkyl group is independently unsubstituted (an "unsubstituted heteroalkyl") or substituted (a "substituted heteroalkyl") with one or more substituents. In n ments, the alkyl group is an unsubstituted heteroCi_2o alkyl.
In certain ments, the heteroalkyl group is an unsubstituted heteroCi_io alkyl. In certain embodiments, the heteroalkyl group is a substituted heteroCi-20 alkyl. In certain embodiments, the heteroalkyl group is an unsubstituted heteroCi_io alkyl.
The term "alkenyl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon double bonds {e.g., 1, 2, 3, or 4 double bonds). In some embodiments, an alkenyl group has 2 to 9 carbon atoms ("C2-9 l"). In some embodiments, an alkenyl group has 2 to 8 carbon atoms ("C2-8 alkenyl"). In some embodiments, an alkenyl group has 2 to 7 carbon atoms ("C2-7 alkenyl"). In some embodiments, an alkenyl group has 2 to 6 carbon atoms ("C2-6 alkenyl"). In some embodiments, an alkenyl group has 2 to 5 carbon atoms ("C2-5 alkenyl"). In some embodiments, an alkenyl group has 2 to 4 carbon atoms ("C2-4 alkenyl"). In some embodiments, an alkenyl group has 2 to 3 carbon atoms ("C2-3 alkenyl"). In some embodiments, an alkenyl group has 2 carbon atoms ("C2 alkenyl"). The one or more carbon-carbon double bonds can be internal (such as in 2- l) or terminal (such as in 1-butenyl). Examples of C2-4 alkenyl groups include ethenyl (C2), 1-propenyl (C3), 2-propenyl (C3), 1-butenyl (C4), 2-butenyl (C4), butadienyl (C4), and the like.
Examples of C2-6 alkenyl groups e the aforementioned C2-4 alkenyl groups as well as pentenyl (C5), ienyl (C5), hexenyl (Ce), and the like. Additional examples of alkenyl include heptenyl (C7), octenyl (Cg), octatrienyl (Cg), and the like. Unless otherwise specified, each instance of an alkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted alkenyl") with one or more substituents. In certain embodiments, the alkenyl group is an unsubstituted C2-10 alkenyl. In certain embodiments, the l group is a substituted C2-10 alkenyl. In an alkenyl group, a C=C double bond for which the stereochemistry is not specified {e.g., -CH=CHCH3 or ) may be an (E)- or (Z)-double bond.
The term "heteroalkenyl" refers to an alkenyl group, which further es at least one atom {e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, en, or sulfur within {i.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain roC2 io alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroC2-9 alkenyl").
In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1 or more atoms within the parent chain ("heteroCi-g alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroCi-? alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or more heteroatoms within the parent chain ("heteroCi-e alkenyl"). In some ments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroCi-s alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroC2-4 alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom within the parent chain ("heteroCi-s alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms within the parent chain ("heteroCi-e alkenyl"). Unless otherwise specified, each ce of a heteroalkenyl group is independently unsubstituted (an "unsubstituted alkenyl") or substituted (a "substituted heteroalkenyl") with one or more substituents. In certain embodiments, the heteroalkenyl group is an unsubstituted Ci-io alkenyl. In certain ments, the heteroalkenyl group is a substituted heteroCi-io l.
The term yl" refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 10 carbon atoms and one or more carbon-carbon triple bonds (e.g., 1, 2, 3, or 4 triple bonds) ("C2-10 alkynyl"). In some embodiments, an alkynyl group has 2 to 9 carbon atoms ("C2-9 alkynyl"). In some embodiments, an alkynyl group has 2 to 8 carbon atoms ("C2-8 alkynyl"). In some embodiments, an alkynyl group has 2 to 7 carbon atoms ("C2-7 alkynyl"). In some embodiments, an alkynyl group has 2 to 6 carbon atoms ("C2-6 l"). In some embodiments, an alkynyl group has 2 to 5 carbon atoms ("C2-5 alkynyl"). In some embodiments, an alkynyl group has 2 to 4 carbon atoms ("C2-4 alkynyl"). In some embodiments, an alkynyl group has 2 to 3 carbon atoms ("C2-3 alkynyl"). In some embodiments, an l group has 2 carbon atoms ("C2 alkynyl"). The one or more carbon-carbon triple bonds can be internal (such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples of C2-4 alkynyl groups include, t limitation, ethynyl (C2), 1-propynyl (C3), 2-propynyl (C3), 1-butynyl (C4), 2-butynyl (C4), and the like. Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkynyl groups as well as pentynyl (C5), hexynyl (Ce), and the like. Additional examples of alkynyl include heptynyl (C7), octynyl (Cg), and the like. Unless otherwise specified, each instance of an alkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or tuted (a "substituted alkynyl") with one or more substituents. In n embodiments, the alkynyl group is an unsubstituted C2-10 alkynyl. In certain embodiments, the alkynyl group is a substituted C2-10 alkynyl.
The term "heteroalkynyl" refers to an alkynyl group, which further includes at least one heteroatom (e.g., 1, 2, 3, or 4 heteroatoms) selected from oxygen, en, or sulfur within (/.e., inserted between adjacent carbon atoms of) and/or placed at one or more terminal position(s) of the parent chain. In certain embodiments, a heteroalkynyl group refers to a group having from 2 to 10 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi io alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-g alkynyl").
In some embodiments, a heteroalkynyl group has 2 to 8 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-g alkynyl"). In some embodiments, a alkynyl group has 2 to 7 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-? alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or more heteroatoms within the parent chain ("heteroCi-e alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain roCi-s l"). In some ments, a alkynyl group has 2 to 4 carbon atoms, at least one triple bond, and lor 2 heteroatoms within the parent chain ("heteroC2-4 alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 3 carbon atoms, at least one triple bond, and 1 heteroatom within the parent chain ("heteroCi-s alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at least one triple bond, and 1 or 2 heteroatoms within the parent chain ("heteroCi-e alkynyl"). Unless otherwise specified, each instance of a heteroalkynyl group is independently unsubstituted (an "unsubstituted alkynyl") or substituted (a "substituted alkynyl") with one or more substituents. In certain embodiments, the heteroalkynyl group is an unsubstituted heteroCi-io alkynyl. In certain embodiments, the heteroalkynyl group is a substituted heteroCi-io alkynyl.
The term "carbocyclyl" or "carbocyclic" refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring carbon atoms ("C3-14 carbocyclyl") and zero heteroatoms in the non-aromatic ring . In some embodiments, a carbocyclyl group has 3 to ring carbon atoms ("C3-10 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms ("C3-8 carbocyclyl"). In some embodiments, a carbocyclyl group has 3 to 7 ring carbon atoms ("€3.7 carbocyclyl"). In some ments, a carbocyclyl group has 3 to 6 ring carbon atoms ("€3.6 carbocyclyl"). In some embodiments, a carbocyclyl group has 4 to 6 ring carbon atoms ("C4-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms ("C5-6 carbocyclyl"). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms ("C5-10 carbocyclyl"). Exemplary €3.6 carbocyclyl groups include, without limitation, cyclopropyl (C3), cyclopropenyl (C3), cyclobutyl (C4), cyclobutenyl (C4), entyl (C5), cyclopentenyl (C5), exyl (Ce), exenyl (Ce), cyclohexadienyl (Ce), and the like.
Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C7), cycloheptenyl (C7), cycloheptadienyl (C7), cycloheptatrienyl (C7), ctyl (Cg), cyclooctenyl (Cg), bicyclo[2.2.1]heptanyl (C7), bicyclo[2.2.2]octanyl (Cg), and the like. Exemplary C3-10 carbocyclyl groups e, without limitation, the aforementioned C3-8 carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10), cyclodecenyl (C10), octahydro-lH-indenyl (C9), decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the ing examples rate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. cyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently unsubstituted (an "unsubstituted carbocyclyl") or substituted (a ituted carbocyclyl") with one or more substituents. In certain embodiments, the carbocyclyl group is an tituted C3-14 carbocyclyl. In n embodiments, the carbocyclyl group is a tuted €3.14 carbocyclyl.
"Carbocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an carbocyclyl group, wherein the point of attachment is on the alkyl moiety.
In some embodiments, "carbocyclyl" is a clic, saturated carbocyclyl group having from 3 to 14 ring carbon atoms ("C3_i4 cycloalkyl"). In some embodiments, a cycloalkyl WO 44620 group has 3 to 10 ring carbon atoms 0 cycloalkyl"). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms ("C3-8 lkyl"). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms ("€3.6 cycloalkyl"). In some embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms ("C4_6 cycloalkyl"). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms ("C5-6 cycloalkyl"). In some embodiments, a lkyl group has 5 to 10 ring carbon atoms ("C5-10 cycloalkyl"). Examples of C5-6 cycloalkyl groups include entyl (C5) and exyl (C5). Examples of €3.6 cycloalkyl groups include the aforementioned Cs_6 cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C4). Examples of €3.8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C?) and cyclooctyl (Cg). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an "unsubstituted cycloalkyl") or substituted (a "substituted cycloalkyl") with one or more substituents. In n embodiments, the cycloalkyl group is an tituted €3.14 cycloalkyl. In certain embodiments, the cycloalkyl group is a substituted C3-14 cycloalkyl.
"Cycloalkylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an cycloalkyl group, wherein the point of attachment is on the alkyl moiety.
The term "heterocyclyl" or "heterocyclic" refers to a radical of a 3- to 14-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring atoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("3-14 membered heterocyclyl"). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A cyclyl group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, d or spiro ring system such as a bicyclic system clic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. Heterocyclyl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heterocyclyl" also includes ring s wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the yclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently unsubstituted (an "unsubstituted heterocyclyl") or substituted (a "substituted heterocyclyl") with one or more substituents. In certain embodiments, the heterocyclyl group is an unsubstituted 3-14 membered heterocyclyl. In certain embodiments, the heterocyclyl group is a substituted 3-14 membered heterocyclyl.
In some embodiments, a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, n each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-10 membered heterocyclyl"). In some ments, a heterocyclyl group is a 5-8 ed omatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-8 membered heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6 membered non-aromatic ring system having ring carbon atoms and 1- 4 ring atoms, wherein each heteroatom is independently selected from en, oxygen, and sulfur ("5-6 membered heterocyclyl"). In some embodiments, the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, , and sulfur. In some ments, the 5-6 membered heterocyclyl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur.
Exemplary 3-membered heterocyclyl groups containing 1 heteroatom e, t limitation, azirdinyl, oxiranyl, and nyl. Exemplary ered heterocyclyl groups containing 1 heteroatom include, without limitation, azetidinyl, yl, and thietanyl.
Exemplary 5-membered heterocyclyl groups containing 1 heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing 2 heteroatoms include, without limitation, dioxolanyl, oxathiolanyl and dithiolanyl. Exemplary ered heterocyclyl groups containing 3 heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing 1 heteroatom e, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups ning 2 heteroatoms e, without limitation, piperazinyl, morpholinyl, dithianyl, and dioxanyl.
Exemplary 6-membered heterocyclyl groups ning 3 heteroatoms include, without limitation, triazinyl. Exemplary 7-membered heterocyclyl groups containing 1 heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered cyclyl groups containing 1 atom e, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary bicyclic heterocyclyl groups include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, tetrahydrobenzothienyl, tetrahydrobenzofuranyl, tetrahydroindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, decahydroisoquinolinyl, octahydrochromenyl, octahydroisochromenyl, decahydronaphthyridinyl, decahydro-l,8-naphthyridinyl, octahydropyrrolo[3,2-b]pyrrole, indolinyl, phthalimidyl, naphthalimidyl, chromanyl, chromenyl, lH-benzo[e][l,4]diazepinyl, 1.4.5.7- tetrahydropyrano[3,4-b]pyrrolyl, 5,6-dihydro-4H-furo[3,2-b]pyrrolyl, 6,7-dihydro-5H- furo[3,2-b]pyranyl, 5,7-dihydro-4H-thieno[2,3-c]pyranyl, hydro-lH-pyrrolo[2,3- b]pyridinyl, 2,3-dihydrofuro[2,3-b]pyridinyl, 4,5,6,7-tetrahydro- lH-pyrrolo[2,3-b]pyridinyl, 4.5.6.7- tetrahydrofuro[3,2-c]pyridinyl, 4,5,6,7-tetrahydrothieno[3,2-b]pyridinyl, 1,2,3,4- tetrahydro-l,6-naphthyridinyl, and the like.
"Heterocyclylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an heterocyclyl group, wherein the point of attachment is on the alkyl moiety.
The term "aryl" refers to a radical of a monocyclic or clic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 7t electrons shared in a cyclic array) having 6-14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system ("C6-14 aryl"). In some ments, an aryl group has 6 ring carbon atoms ("Ce aryl"; e.g., phenyl). In some embodiments, an aryl group has 10 ring carbon atoms ("Cio aryl"; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). In some embodiments, an aryl group has 14 ring carbon atoms ("C14 aryl"; e.g., anthracyl). "Aryl" also es ring systems wherein the aryl ring, as defined above, is fused with one or more yclyl or heterocyclyl groups wherein the radical or point of ment is on the aryl ring, and in such instances, the number of carbon atoms continue to ate the number of carbon atoms in the aryl ring system. Unless otherwise specified, each instance of an aryl group is ndently unsubstituted (an "unsubstituted aryl") or substituted (a "substituted aryl") with one or more substituents. In certain embodiments, the aryl group is an unsubstituted Ce-u aryl- In certain embodiments, the aryl group is a substituted Ce-u aryl.
"Arylalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by an aryl group, wherein the point of attachment is on the alkyl moiety.
WO 44620 The term "heteroaryl" refers to a radical of a 5-14 membered monocyclic or polycyclic (e.g., bicyclic, tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 71 electrons shared in a cyclic array) having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is ndently selected from nitrogen, oxygen, and sulfur ("5-14 ed aryl"). In heteroaryl groups that contain one or more nitrogen atoms, the point of ment can be a carbon or nitrogen atom, as valency permits. Heteroaryl polycyclic ring systems can include one or more heteroatoms in one or both rings. "Heteroaryl" includes ring systems wherein the heteroaryl ring, as d above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members ue to designate the number of ring members in the heteroaryl ring system. "Heteroaryl" also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring g a heteroatom (e.g., 2-indolyl) or the ring that does not contain a heteroatom (e.g., 5-indolyl).
In some ments, a heteroaryl group is a 5-10 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently ed from nitrogen, oxygen, and sulfur ("5-10 membered heteroaryl"). In some embodiments, a heteroaryl group is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from en, oxygen, and sulfur ("5-8 membered aryl"). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each atom is independently ed from nitrogen, oxygen, and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 ed heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently unsubstituted (an stituted heteroaryl") or substituted (a "substituted heteroaryl") with one or more substituents. In certain embodiments, the heteroaryl group is an unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is a substituted 5-14 membered heteroaryl.
Exemplary 5-membered heteroaryl groups containing 1 heteroatom include, t limitation, yl, furanyl, and thiophenyl. Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, lyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing 3 atoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary ered heteroaryl groups containing 4 atoms include, without limitation, tetrazolyl. Exemplary 6- membered heteroaryl groups containing 1 heteroatom include, without limitation, pyridinyl.
Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing 3 or 4 heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7- membered heteroaryl groups containing 1 heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. ary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, lyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, iadiazolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, yridinyl, inyl, quinolinyl, isoquinolinyl, inyl, quinoxalinyl, phthalazinyl, and quinazolinyl. Exemplary tricyclic heteroaryl groups include, without limitation, phenanthridinyl, dibenzofuranyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, and phenazinyl.
"Heteroaryalkyl" is a subset of "alkyl" and refers to an alkyl group substituted by a heteroaryl group, wherein the point of attachment is on the alkyl moiety.
The term "silyl" refers to the group -Si(Raa)3, wherein Raa is as defined herein.
The term "boronyl" refers to boranes, boronic acids, boronic esters, borinic acids, and borinic esters, e.g., l groups of the a -B(Raa)2, -B(ORcc)2, and -BRaa(ORcc), n Raa and Rcc are as defined herein.
The term "phosphine" refers to the group -P(RCC)3, wherein Rcc is as defined herein. An exemplary phosphino group is triphenylphosphine.
The term "phosphono" refers to the group -0(P=0)(0Rcc)Raa, wherein Raa and Rcc are as defined herein.
The term "phosphoramido" refers to the group -0(P=0)(N(Rbb)2)2, wherein each Rbb is as defined herein.
The term "stannyl" refers to the group c)3, wherein Rcc is as defined herein.
The term "germyl" refers to the group -Ge(Rcc)3, n Rcc is as defined herein.
The term "arsenyl" refers to the group c)3, n Rcc is as defined herein.
The term "oxo" refers to the group =0, and the term xo" refers to the group =S.
The term "halo" or "halogen" refers to fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), or iodine (iodo, -I).
The term "hydroxyl" or "hydroxy" refers to the group -OH. The term "substituted yl" or "substituted hydroxyl," by extension, refers to a hydroxyl group wherein the oxygen atom directly attached to the parent molecule is substituted with a group other than hydrogen, and includes groups selected from -ORaa, -ON(Rbb)2, -OC(=0)SRaa, -OC(=0)Raa, -OC02Raa, -OC(=0)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -OS(=0)Raa, -OS02Raa, -OSi(Raa)3, -OP(Rcc)2, -OP(Rcc)3+X", cc)2, -OP(ORcc)3+X", -OP(=0)(Raa)2, -OP(=0)(ORcc)2, and -0P(=0)(N(Rbb)2)2, wherein X", Raa, Rbb, and Rcc are as defined herein.
The term "amino" refers to the group -NH2. The term "substituted amino," by extension, refers to a monosubstituted amino, a disubstituted amino, or a trisubstituted amino. In certain embodiments, the "substituted amino" is a monosubstituted amino or a disubstituted amino group.
The term "monosubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is substituted with one hydrogen and one group other than hydrogen, and includes groups selected from -NH(Rbb), -NHC(=0)Raa, -NHC02Raa, -NHC(=0)N(Rbb)2, NRbb)N(Rbb)2, -NHS02Raa, 0)(ORcc)2, and -NHP(=0)(N(Rbb)2)2, wherein Raa, Rbb and Rcc are as defined herein, and wherein Rbb of the group b) is not hydrogen.
The term "disubstituted amino" refers to an amino group wherein the en atom ly attached to the parent molecule is substituted with two groups other than hydrogen, and includes groups selected from -N(Rbb)2, -NRbbC(=0)Raa, -NRbbC02Raa, -NRbbC(=0)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -NRbbS02Raa, -NRbbP(=0)(0Rcc)2, and -NRbbP(=0)(N(Rbb)2)2, wherein Raa, Rbb, and Rcc are as d herein, with the proviso that the nitrogen atom directly attached to the parent molecule is not substituted with hydrogen.
The term "trisubstituted amino" refers to an amino group wherein the nitrogen atom directly attached to the parent molecule is tuted with three , and includes groups selected from -N(Rbb)3 and -N(Rbb)3+X-, wherein Rbb and X- are as defined herein.
The term "sulfonyl" refers to a group selected from -S02N(Rbb)2, -S02Raa, and - S02ORaa, wherein Raa and Rbb are as defined herein.
The term "sulfinyl" refers to the group -S(=0)Raa, wherein Raa is as defined .
The term "acyl" refers to a group having the general formula -C(=0)R , ORxl, -C(=0)C(=0)Rxl, -C(=0)SRxl, -C(=0)N(Rxl)2, -C(=S)RX1, -C(=S)N(RX1)2, -C(=S)0(Rx1), -C(=S)S(RX1), -C(=NRX1)RX1, -C(=NRxl)ORxl, X1)SRX1, and -C(=NRX1)N(RX1)2, wherein RX1 is hydrogen; halogen; substituted or unsubstituted hydroxyl; substituted or unsubstituted thiol; substituted or unsubstituted amino; substituted or unsubstituted acyl, cyclic or acyclic, tuted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or tituted, branched or unbranched heteroaliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkyl; cyclic or acyclic, substituted or unsubstituted, branched or unbranched alkenyl; substituted or tituted alkynyl; substituted or unsubstituted aryl, substituted or tituted heteroaryl, aliphaticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, heteroarylthioxy, mono- or di- aliphaticamino, mono- or di- heteroaliphaticamino, mono- or dialkylamino , mono- or di- heteroalkylamino, mono- or di-arylamino, or mono- or diheteroarylamino ; or two R groups taken together form a 5- to 6-membered heterocyclic ring.
Exemplary acyl groups include aldehydes (-CHO), carboxylic acids ), ketones, acyl halides, esters, amides, imines, carbonates, carbamates, and ureas. Acyl substituents include, but are not limited to, any of the tuents described herein, that result in the formation of a stable moiety (e.g., aliphatic, alkyl, alkenyl, alkynyl, heteroaliphatic, heterocyclic, aryl, heteroaryl, acyl, oxo, imino, thiooxo, cyano, isocyano, amino, azido, nitro, hydroxyl, thiol, halo, aliphaticamino, heteroaliphaticamino, alkylamino, heteroalkylamino, arylamino, heteroarylamino, alkylaryl, kyl, ticoxy, heteroaliphaticoxy, alkyloxy, heteroalkyloxy, aryloxy, heteroaryloxy, aliphaticthioxy, heteroaliphaticthioxy, alkylthioxy, heteroalkylthioxy, arylthioxy, arylthioxy, acyloxy, and the like, each of which may or may not be further substituted).
The term "carbonyl" refers a group wherein the carbon directly attached to the parent molecule is sp hybridized, and is substituted with an oxygen, nitrogen or sulfur atom, e.g., a group selected from ketones (e.g., -C(=0)Raa), carboxylic acids (e.g., -COiH), aldehydes (- CHO), esters (e.g., -C02Raa,-C(=0)SRaa, SRaa), amides (e.g., -C(=0)N(Rbb)2, - C(=0)NRbbS02Raa, N(Rbb)2), and imines (e.g., -C(=NRbb)Raa, -C(=NRbb)ORaa), - C(=NRbb)N(Rbb)2), wherein Raa and Rbb are as defined herein.
Affixing the suffix "-ene" to a group tes the group is a divalent moiety, e.g., alkylene is the divalent moiety of alkyl, alkenylene is the divalent moiety of alkenyl, alkynylene is the nt moiety of alkynyl, alkylene is the divalent moiety of heteroalkyl, heteroalkenylene is the divalent moiety of heteroalkenyl, heteroalkynylene is the nt moiety of heteroalkynyl, carbocyclylene is the divalent moiety of carbocyclyl, heterocyclylene is the divalent moiety of heterocyclyl, arylene is the nt moiety of aryl, and heteroarylene is the divalent moiety of heteroaryl.
A group is optionally substituted unless expressly provided otherwise. The term nally substituted" refers to being substituted or unsubstituted. In certain embodiments, alkyl, alkenyl, alkynyl, heteroalkyl, alkenyl, heteroalkynyl, yclyl, heterocyclyl, aryl, and heteroaryl groups are optionally substituted. "Optionally substituted" refers to a group which may be substituted or unsubstituted (e.g., "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl, "substituted" or "unsubstituted" alkyl, "substituted" or "unsubstituted" heteroalkenyl, "substituted" or "unsubstituted" heteroalkynyl, "substituted" or "unsubstituted" yclyl, "substituted" or "unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl or "substituted" or "unsubstituted" heteroaryl group). In general, the term "substituted" means that at least one hydrogen present on a group is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, ation, or other reaction.
Unless otherwise indicated, a "substituted" group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is tuted, the substituent is either the same or different at each position. The term "substituted" is contemplated to include substitution with all sible tuents of organic compounds, and includes any of the substituents described herein that s in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. The invention is not intended to be limited in any manner by the ary substituents bed herein.
Exemplary carbon atom tuents include, but are not limited to, halogen, -CN, -N02, -N3, -S02H, -S03H, -OH, -ORaa, b)2, -N(Rbb)2, -N(Rbb)3+X", -N(ORcc)Rbb, -SH, -SRaa, -SSRCC, -C(=0)Raa, -C02H, -CHO, -C(ORcc)3, -C02Raa, -0C(=0)Raa, -0C02Raa, -C(=0)N(Rbb)2, -0C(=0)N(Rbb)2, -NRbbC(=0)Raa, -NRhhC02Raa, -NRbbC(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -C(=NRbb)N(Rbb)2, -OC(=NRbb)N(Rbb)2, -NRbbC(=NRbb)N(Rbb)2, -C(=0)NRbbS02Raa, -NRbbS02Raa, -S02N(Rbb)2, -S02Raa, -S020Raa, -0S02Raa, -S(=0)Raa, -0S(=0)Raa, -Si(Raa)3, -OSi(Raa)3 -C(=S)N(Rbb)2, -C(=0)SRaa, -C(=S)SRaa, )SRaa, -SC(=0)SRaa, -0C(=0)SRaa, -SC(=0)0Raa, -SC(=0)Raa, -P(=0)(Raa)2, -P(=0)(0Rcc)2,-0P(=0)(Raa)2, -0P(=0)(0Rcc)2, -P(=0)(N(Rbb)2)2, -0P(=0)(N(Rbb)2)2, -NRbbP(=0)(Raa)2, (=0)(0Rcc)2, -NRbbP(=0)(N(Rbb)2)2, -P(RCC)2, -P(ORcc)2, -P(RCC)3+X", -P(ORcc)3+X", -P(Rcc)4, -P(ORcc)4,-OP(Rcc)2, -OP(Rcc)3+X", -OP(ORcc)2, -OP(ORcc)3+X", -OP(Rcc)4, -OP(ORcc)4, )2, -B(ORcc)2, -BRaa(ORcc), CMo alkyl, CMo perhaloalkyl, C2_io alkenyl, C2. alkynyl, heteroCi_io alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, C3_io carbocyclyl, 3-14 membered heterocyclyl, Ce-u aryl, and 5-14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is ndently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X- is a counterion; or two geminal hydrogens on a carbon atom are replaced with the group =0, =S, =NN(Rbb)2, =NNRbbC(=0)Raa, =NNRbbC(=0)ORaa, S(=0)2Raa, =NRbb, or =NORcc; each instance of Raa is, independently, selected from Cmo alkyl, Cmo perhaloalkyl, C2-10 alkenyl, C2-10 alkynyl, Ci-10 alkyl, heteroC2-io l, heteroC2-io alkynyl, C3-10 yclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl, or two R aa groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, l, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rbb is, ndently, selected from en, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, -S02Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -S02N(Rcc)2, -S02Rcc, -S020Rcc, -SORaa, -C(=S)N(Rcc)2, -C(=0)SRcc, -C(=S)SRcc, -P(=0)(Raa)2, -P(=0)(0Rcc)2, -P(=0)(N(Rcc)2)2, Cmo alkyl, Cmo perhaloalkyl, Cmo l, Cmo alkynyl, heteroCmo alkyl, heteroC2_io alkenyl, heteroC2_i oalkynyl, C;vm carbocyclyl, 3-14 membered heterocyclyl, Ce-w aryl, and 5-14 membered heteroaryl, or two Rbb groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is ndently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; wherein X- is a counterion; each instance of Rcc is, independently, selected from hydrogen, Cmo alkyl, Cmo perhaloalkyl, Cmo alkenyl, Cmo alkynyl, heteroC mo alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, Cmo carbocyclyl, 3-14 membered cyclyl, Co-14 aryl, and 5-14 membered heteroaryl, or two Rcc groups are joined to form a 3-14 ed heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, alkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups; each instance of Rdd is, independently, selected from halogen, -CN, -N02, -N3, -S02H, -SO3H, -OH, -ORee, -ON(Rff)2, -N(Rff)2, -N(Rff)3+X", -N(ORee)Rff, -SH, -SRee, , -C(=0)Ree, -C02H, -C02Ree, -OC(=0)Ree, -OC02Ree, -C(=0)N(Rff)2, -OC(=0)N(Rff)2, -NRffC(=0)Ree, 02Ree, -NRffC(=0)N(Rff)2, -C(=NRff)ORee, -OC(=NRff)Ree, -OC(=NRff)ORee, -C(=NRff)N(Rff)2, -OC(=NRff)N(Rff)2, -NRffC(=NRff)N(Rff)2, -NRffS02Ree, -S02N(Rff)2, -S02Ree, ee, -OS02Ree, -S(=0)Ree, -Si(Ree)3, -OSi(Ree)3, -C(=S)N(Rff)2, -C(=0)SRee, -C(=S)SRee, )SRee, -P(=0)(ORee)2, -P(=0)(Ree)2, -OP(=0)(Ree)2, -OP(=0)(ORee)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2_6 alkenyl, C2_6 alkynyl, heteroCi_6 alkyl, heteroCi-e alkenyl, heteroCi-e alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl, -10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups, or two geminal Rdd substituents can be joined to form =0 or =S; wherein X- is a rion; each instance of Ree is, independently, selected from Ci_6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2-6 alkynyl, heteroCi_6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, €3.10 carbocyclyl, Ce-io aryl, 3-10 ed heterocyclyl, and 3-10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and aryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of R is, ndently, ed from hydrogen, Ci_6 alkyl, Ci_6 ff perhaloalkyl, C2-6 l, C2-6 alkynyl, heteroCi_6 alkyl, heteroC2-6 alkenyl, heteroC2-6 alkynyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, Ce-io aryl and 5-10 membered heteroaryl, or two Rff groups are joined to form a 3-10 membered heterocyclyl or 5-10 ed heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, alkenyl, heteroalkynyl, yclyl, heterocyclyl, aryl, and heteroaryl is ndently substituted with 0, 1, 2, 3, 4, or 5 Rgg groups; each instance of Rgg is, independently, halogen, -CN, -NO2, -N3, -SO2H, -SO3H, -OH, -OC1-6 alkyl, -ON(Ci_6 alkyl)2, 6 alkyl)2, -N(Ci_6 alkyl)3+X-, .6 alkyl)2+X-, -NH2(Ci_6 alkyl)+X", -NH3+X", -N(OCi.6 alkyl)(Ci.6 alkyl), -N(OH)(Ci_6 alkyl), ), -SH, -SC1.6 alkyl, -SS(Ci-6 alkyl), -C(=0)(Ci.6 , -C02H, -C02(Ci^ alkyl), )(Ci_ 6 alkyl), -0C02(Ci-6 alkyl), -C(=0)NH2, -C(=0)N(Ci.6 alkyl)2, -OC(=0)NH(Ci.6 alkyl), -NHC(=0)(Ci_6 alkyl), -N(Ci.6 alkyl)C(=0)( Ci.6 alkyl), -NHC02(Ci^ alkyl), -NHC(=0)N(Ci_ 6 alkyl)2, -NHC(=0)NH(Ci_6 alkyl), -NHC(=0)NH2, -C(=NH)0(Ci.6 alkyl), -OC(=NH)(Ci.6 alkyl), -OC(=NH)OCi-6 alkyl, -C(=NH)N(Ci.6 2, -C(=NH)NH(Ci-6 alkyl), -C(=NH)NH2, -OC(=NH)N(Ci.6 alkyl)2, -OC(=NH)NH(Ci-6 alkyl), -OC(=NH)NH2, -NHC(=NH)N(Ci.6 alkyl)2, -NHC(=NH)NH2, -NHS02(Ci.6 alkyl), -S02N(Ci.6 alkyl)2, -S02NH(Ci_6 , -SO2NH2, -S02(Ci_6 alkyl), -S020(Ci_6 alkyl), -0S02(Ci.6 alkyl), -SO(Ci.6 alkyl), -Si(Ci_6 alkyl)3, -OSi(Ci.6 alkyl)3 -C(=S)N(Ci-6 alkyl)2, C(=S)NH(Ci.6 alkyl), C(=S)NH2, -C(=0)S(Ci-6 alkyl), -C(=S)SCi.6 alkyl, -SC(=S)SCi.6 alkyl, -P(=0)(OCi-6 alkyl)2, -P(=0)(Ci.6 alkyl)2, -OP(=0)(Ci_6 alkyl)2, -OP(=0)(OCi_6 alkyl)2, Ci_6 alkyl, Ci_6 perhaloalkyl, C2-6 alkenyl, C2-6 l, heteroCi_6 alkyl, heteroCi-e alkenyl, heteroCi-e alkynyl, C3-10 carbocyclyl, Ce-io aryl, 3-10 membered heterocyclyl, 5-10 membered heteroaryl; or two geminal Rgg substituents can be joined to form =0 or =S; wherein X- is a counterion.
Nitrogen atoms can be substituted or tituted as valency permits, and include primary, secondary, tertiary, and quaternary nitrogen atoms. Exemplary nitrogen atom substituents include, but are not limited to, hydrogen, -OH, -ORaa, -N(RCC)2, -CN, -C(=0)Raa, -C(=0)N(Rcc)2, a, -S02Raa, -C(=NRbb)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, Rcc)2, -S02Rcc, -S02ORcc, -SORaa, -C(=S)N(Rcc)2, SRcc, -C(=S)SRcc, -P(=0)(ORcc)2, -P(=0)(Raa)2, -P(=0)(N(Rcc)2)2, Ci-io alkyl, Cuo perhaloalkyl, C2.i0 alkenyl, C2-io alkynyl, heteroCi-ioalkyl, heteroC2-ioalkenyl, heteroC2-ioalkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-u aryl, and 5-14 ed heteroaryl, or two Rcc groups attached to an N atom are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 Rdd groups, and n Raa, Rbb, Rcc and Rdd are as defined herein.
In certain embodiments, the substituent present on the nitrogen atom is an nitrogen protecting group (also referred to herein as an "amino protecting group"). Nitrogen protecting groups include, but are not limited to, -OH, -ORaa, -N(RCC)2, -C(=0)Raa, -C(=0)N(Rcc)2, -C02Raa, a, -C(=NRcc)Raa, -C(=NRcc)ORaa, -C(=NRcc)N(Rcc)2, -S02N(Rcc)2, -S02Rcc, -S02ORcc, , -C(=S)N(Rcc)2, -C(=0)SRcc, SRcc, Cuo alkyl {e.g., aralkyl, heteroaralkyl), C2-io alkenyl, C2-io alkynyl, heteroCi_io alkyl, heteroC2_io alkenyl, heteroC2_io alkynyl, C3-10 carbocyclyl, 3-14 membered heterocyclyl, Ce-14 aryl, and 5-14 membered heteroaryl groups, wherein each alkyl, alkenyl, l, heteroalkyl, alkenyl, heteroalkynyl, carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or 5 Rdd groups, and wherein Raa, Rbb, Rcc and Rdd are as defined herein. Nitrogen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, incorporated herein by reference.
For example, nitrogen ting groups such as amide groups {e.g., Raa) include, but are not limited to, formamide, ide, acetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylpropanamide, picolinamide, 3- pyridylcarboxamide, oylphenylalanyl derivative, benzamide, p-phenylbenzamide, henylacetamide , ophenoxyacetamide, acetoacetamide, (N’- dithiobenzyloxyacylamino)acetamide, ydroxyphenyl)propanamide, 3-(onitrophenyl )propanamide, 2-methyl(o-nitrophenoxy)propanamide, 2-methyl(ophenylazophenoxy )propanamide, 4-chlorobutanamide, 3-methylnitrobutanamide, onitrocinnamide , N-acetylmethionine derivative, o-nitrobenzamide and o- (benzoyloxymethyl)benzamide.
Nitrogen protecting groups such as carbamate groups (e.g., -C(=0)0Raa) include, but are not limited to, methyl ate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo)fluorenylmethyl carbamate, 9-(2,7-dibromo)fluoroenylmethyl carbamate, 2,7-di-t-butyl- [9-(10,10-dioxo-10,10,10,10-tetrahydrothioxanthyl)]methyl carbamate (DBD-Tmoc), 4- yphenacyl carbamate (Phenoc), 2,2,2-trichloroethyl carbamate (Troc), 2- trimethylsilylethyl carbamate (Teoc), 2-phenylethyl carbamate (hZ), l-(l-adamantyl)-!- ethyl carbamate (Adpoc), l,l-dimethylhaloethyl carbamate, 1,1-dimethyl-2,2- dibromoethyl carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate (TCBOC), 1- -l-(4-biphenylyl)ethyl carbamate (Bpoc), l-(3,5-di-t-butylphenyl)-l-methylethyl carbamate (t-Bumeoc), 2-(2'- and 4'-pyridyl)cthyl carbamate (Pyoc), 2-(N,N- dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate (BOC or Boc), 1-adamantyl ate (Adoc), vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolyl carbamate, N- hydroxypiperidinyl carbamate, alkyldithio carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz), p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl carbamate, 2-methylthioethyl carbamate, ylsulfonylethyl ate, 2-(p-toluenesulfonyl)ethyl carbamate, [2-(l,3-dithianyl)]methyl carbamate , 4-methylthiophenyl carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc), 2- phosphonioethyl carbamate , 2-triphenylphosphonioisopropyl carbamate (Ppoc), 1,1- dimethylcyanoethyl carbamate, m-chloro-p-acyloxybenzyl carbamate, p- (dihydroxyboryl)benzyl carbamate, 5-benzisoxazolylmethyl carbamate, 2-(trifluoromethyl) chromonylmethyl carbamate ), m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate, o-nitrobenzyl carbamate, 3,4-dimethoxynitrobenzyl ate, phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl ate, cyclopropylmethyl carbamate, pdecyloxybenzyl ate, 2,2-dimethoxyacylvinyl carbamate, - dimethylcarboxamido)benzyl carbamate, l,l-dimethyl(N,N-dimethylcarboxamido)propyl carbamate, methylpropynyl ate, di(2-pyridyl)methyl carbamate, nylmethyl carbamate, 2-iodoethyl carbamate, isoborynl carbamate, isobutyl carbamate, isonicotinyl carbamate, methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl carbamate, 1- methylcyclohexyl carbamate, 1-methylcyclopropylmethyl carbamate, 1-methyl(3,5- oxyphenyl)ethyl carbamate, 1-methyl-l-(p-phenylazophenyl)ethyl carbamate, 1-methyl ethyl carbamate, 1-methyl-l-(4-pyridyl)ethyl carbamate, phenyl carbamate, p- (phenylazo)benzyl carbamate, 2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl ate, and 2,4,6-trimethylbenzyl carbamate.
Nitrogen protecting groups such as sulfonamide groups {e.g., -S(=0)2Raa) include, but are not limited to, p-toluenesulfonamide (Ts), benzenesulfonamide, 2,3,6-trimethyl methoxybenzenesulfonamide (Mtr), 2,4,6-trimethoxybenzenesulfonamide (Mtb), 2,6-dimethyl methoxybenzenesulfonamide (Pme), 2,3,5,6-tetramethylmethoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4,6-trimethylbenzenesulfonamide (Mts), 2,6- oxymethylbenzenesulfonamide (iMds), 2,2,5,7,8-pentamethylchromansulfonamide (Pmc), methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES), 9- anthracenesulfonamide, 8/-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and phenacylsulfonamide.
Other nitrogen protecting groups include, but are not limited to, phenothiazinyl-(lO)- acyl derivative, N'-p-1o 1 ucncsu 1 fony 1 aminoacyl derivative, N'-phcnylaminothioacyl derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine derivative, 4,5-diphenyloxazolin one, N-phthalimide, N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide, N-2,5- dimethylpyrrole, N-l,l,4,4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1,3-dimethyl-1,3,5-triazacyclohexanone, 5-substituted 1,3-dibenzyl-1,3,5-triazacyclohexan one, 1-substituted 3,5-dinitropyridone, N-methylamine, N-allylamine, N-[2- (trimethylsilyl)ethoxy]methylamine (SEM), Nacetoxypropylamine, N-(l-isopropylnitro oxopyroolinyl)amine, quaternary ammonium salts, N-benzylamine, N-di(4- methoxyphenyl)methylamine, Ndibenzosuberylamine, N-triphenylmethylamine (Tr), N-[(4- methoxyphenyl)diphenylmethyl]amine (MMTr), Nphenylfluorenylamine (PhF), N-2,7- dichlorofluorenylmethyleneamine, N-ferrocenylmethylamino (Fcm), Npicolylamino N’- oxide, N-l,l-dimethylthiomethyleneamine, N-benzylideneamine, N-pmethoxybenzylideneamine , N-diphenylmethyleneamine, N- [(2-pyridyl)mesityl] methyleneamine, N-(N’ ,N’ -dimethylaminomethylene)amine, N,N’ -isopropylidenediamine, N-pnitrobenzylideneamine , N-salicylideneamine, Nchlorosalicylideneamine, hloro hydroxyphenyl)phenylmethyleneamine, N-cyclohexylideneamine, N-(5,5-dimethyloxo-lcyclohexenyl )amine, N-borane derivative, N-diphenylborinic acid tive, N- [phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper chelate, N-zinc chelate, N- nitroamine, N-nitrosoamine, amine N-oxide, diphenylphosphinamide (Dpp), ylthiophosphinamide (Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates, dibenzyl phosphoramidate, diphenyl phosphoramidate, esulfenamide, onitrobenzenesulfenamide (Nps), 2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide, 2-nitromethoxybenzenesulfenamide, triphenylmethylsulfenamide, and opyridinesulfenamide (Npys). In certain embodiments, a nitrogen protecting group is benzyl (Bn), tert-butyloxycarbonyl (BOC), carbobenzyloxy (Cbz), 9-flurenylmethyloxycarbonyl (Fmoc), trifluoroacetyl, triphenylmethyl, acetyl (Ac), benzoyl (Bz), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), 2,2,2- trichloroethyloxycarbonyl (Troc), triphenylmethyl (Tr), tosyl (Ts), brosyl (Bs), nosyl (Ns), mesyl (Ms), triflyl (Tf), or dansyl (Ds).
In certain embodiments, the tuent present on an oxygen atom is an oxygen protecting group (also referred to herein as an xyl protecting group"). Oxygen protecting groups include, but are not d to, -Raa, -N(Rbb)2, SRaa, Raa, -C02Raa, -C(=0)N(Rbb)2, -C(=NRbb)Raa, bb)ORaa, -C(=NRbb)N(Rbb)2, -S(=0)Raa, -S02Raa, -Si(Raa)3, -P(Rcc)2, -P(Rcc)3+X",-P(ORcc)2, -P(ORcc)3+X", -P(=0)(Raa)2, -P(=0)(0Rcc)2, and -P(=0)(N(Rbb) 2)2, wherein X-, Raa, Rbb, and Rcc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999, incorporated herein by reference.
Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), thiomethyl (MTM), t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM), pmethoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM), guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM), siloxymethyl, 2-methoxyethoxymethyl (MEM), trichloroethoxymethyl, bis(2-chloroethoxy)methyl, 2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP), 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1- methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP), 4-methoxytetrahydrothiopyranyl, 4- methoxytetrahydrothiopyranyl S ,S de, 1 - [(2-chloromethyl)phenyl] methoxypiperidin- 4-yl (CTMP), l,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2,3,3a,4,5,6,7,7aoctahydro-7 ,8,8-trimethyl-4,7-methanobenzofuranyl, 1-ethoxyethyl, l-(2-chloroethoxy)ethyl, 1 -methyl-1 xyethyl, 1 -methyl-1 -benzyloxyethyl, 1 -methyl-1 -benzyloxyfluoroethyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, 2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl, 3,4-dimethoxybenzyl, onitrobenzyl , p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2- picolyl, 4-picolyl, 3-methylpicolyl N-oxido, diphenylmethyl, p,p’-dinitrobenzhydryl, 5- osuberyl, triphenylmethyl, thyldiphenylmethyl, p-methoxyphenyldiphenylmethyl, di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl, 4-(4’- bromophenacyloxyphenyl)diphenylmethyl, 4,4',4"-tris(4,5-dichlorophthalimidophenyl)methyl, 4,4',4''-tris(levulinoyloxyphenyl)methyl, 4,4',4"-tris(benzoyloxyphenyl)methyl, 3-(imidazol-lyl )bis(4',4"-dimethoxyphenyl)methyl, l,l-bis(4-methoxyphenyl)-l'-pyrenylmethyl, ryl, 9- (9-phenyl)xanthenyl, 9-(9-phenyloxo)anthryl, l,3-benzodithiolanyl, benzisothiazolyl S,S- o, trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl (TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl (DEIPS), dimethylthexylsilyl, tbutyldimethylsilyl ), t-butyldiphenylsilyl (TBDPS), zylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl , t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate, acetate, acetate, dichloroacetate, trichloroacetate, trifluoroacetate, yacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, 3- phenylpropionate, 4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate (levulinoyldithioacetal), pivaloate, adamantoate, crotonate, 4-methoxycrotonate, benzoate, pphenylbenzoate , 2,4,6-trimethylbenzoate (mesitoate), methyl ate, 9-fluorenylmethyl carbonate (Fmoc), ethyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), methylsilyl)ethyl carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec), 2-(triphenylphosphonio) ethyl ate (Peoc), isobutyl carbonate, vinyl carbonate, allyl carbonate, t-butyl carbonate (BOC or Boc), p-nitrophenyl carbonate, benzyl carbonate, p-methoxybenzyl carbonate, 3,4- dimethoxybenzyl carbonate, o-nitrobenzyl carbonate, p-nitrobenzyl ate, S-benzyl thiocarbonate, 4-ethoxynapththyl carbonate, methyl dithiocarbonate, 2-iodobenzoate, 4- azidobutyrate, 4-nitromethylpentanoate, o-(dibromomethyl)benzoate, 2- formylbenzenesulfonate, hylthiomethoxy)ethyl, 4-(methylthiomethoxy)butyrate, 2- (methylthiomethoxymethyl)benzoate, 2,6-dichloromethylphenoxyacetate, 2,6-dichloro (1,1,3,3 methylbutyl)phenoxyacetate, 2,4-bis( 1,1 -dimethylpropyl)phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinoate, (E)methylbutenoate, o- (methoxyacyl)benzoate, thoate, nitrate, alkyl ,N’-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate, borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate, sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate (Ts). In certain embodiments, an oxygen protecting group is silyl. In certain embodiments, an oxygen protecting group is t- butyldiphenylsilyl (TBDPS), t-butyldimethylsilyl (TBDMS), triisoproylsilyl (TIPS), triphenylsilyl (TPS), triethylsilyl (TES), trimethyl silyl (TMS), propylsiloxymethyl (TOM), acetyl (Ac), benzoyl (Bz), allyl carbonate, 2,2,2-trichloroethyl carbonate (Troc), 2- trimethylsilylethyl carbonate, methoxymethyl (MOM), 1-ethoxyethyl (EE), 2-methyoxy propyl (MOP), 2,2,2-trichloroethoxyethyl, 2-methoxyethoxymethyl (MEM), 2- trimethylsilylethoxymethyl (SEM), methylthiomethyl (MTM), tetrahydropyranyl (THP), tetrahydrofuranyl (THE), p-methoxyphenyl (PMP), triphenylmethyl (Tr), methoxytrityl (MMT), oxytrityl (DMT), allyl, p-methoxybenzyl (PMB), t-butyl, benzyl (Bn), allyl, or pivaloyl (Piv).
In certain embodiments, the substituent present on a sulfur atom is a sulfur protecting group (also referred to as a "thiol protecting group"). Sulfur ting groups include, but are not limited to, -Raa, -N(Rbb)2, -C(=0)SRaa, Raa, -C02Raa, -C(=0)N(Rbb)2, -C(=NRbb)Raa, -C(=NRbb)ORaa, bb)N(Rbb)2, -S(=0)Raa, -S02Raa, -Si(Raa)3, -P(RCC)2, -P(Rcc)3+X-,-P(ORcc)2, -P(ORcc)3+X_, -P(=0)(Raa)2, -P(=0)(0Rcc)2, and -P(=0)(N(Rbb) 2)2, wherein Raa, Rbb, and Rcc are as defined herein. Sulfur protecting groups are well known in the art and include those bed in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 edition, John Wiley & Sons, 1999, orated herein by reference. In WO 44620 certain embodiments, a sulfur protecting group is acetamidomethyl, t-Bu, 3-nitropyridine sulfenyl, 2-pyridine-sulfenyl, or triphenylmethyl.
A "counterion" or "anionic rion" is a negatively charged group ated with a positively charged group in order to maintain electronic neutrality. An anionic counterion may be monovalent (/.
The term "leaving group" is given its ordinary meaning in the art of synthetic organic chemistry and refers to an atom or a group capable of being displaced by a nucleophile. See, for example, Smith, March’s Advanced Organic Chemistry 6th ed. (501-502). Examples of suitable leaving groups include, but are not limited to, halogen (such as F, Cl, Br, or I e)), alkoxycarbonyloxy, aryloxycarbonyloxy, alkanesulfonyloxy, arenesulfonyloxy, arbonyloxy (e.g., acetoxy), arylcarbonyloxy, aryloxy, methoxy, E,O-dimethy 1 hydroxy 1 amino, pixyl, and haloformates. In some cases, the leaving group is a ic acid ester, such as toluenesulfonate (tosylate, -OTs), methanesulfonate (mesylate, -OMs), pbromobenzenesulfonyloxy (brosylate, -OBs), -0S(=0)2(CF2)3CF3 late, -ONf), or trifluoromethanesulfonate (triflate, -OTf). In some cases, the leaving group is a brosylate, such as p-bromobenzenesulfonyloxy. In some cases, the leaving group is a nosylate, such as 2- enzenesulfonyloxy.The leaving group may also be a phosphineoxide (e.g., formed during a Mitsunobu reaction) or an internal leaving group such as an epoxide or cyclic sulfate. Other nonlimiting examples of leaving groups are water, ammonia, alcohols, ether moieties, thioether es, zinc halides, magnesium moieties, diazonium salts, and copper moieties. Further exemplary leaving groups include, but are not limited to, halo (e.g., chloro, bromo, iodo) and activated substituted hydroxyl groups (e.g., -0C(=0)SRaa, -0C(=0)Raa, 11, - 0C(=0)N(Rbb)2, -OC(=NRbb)Raa, -OC(=NRbb)ORaa, -OC(=NRbb)N(Rbb)2, -0S(=0)Raa, - 0S02Raa, -OP(Rcc)2, -OP(Rcc)3, -0P(=0)2Raa, -0P(=0)(Raa)2, -0P(=0)(0Rcc)2, - 0P(=0)2N(Rbb)2, and -0P(=0)(NRbb)2, wherein Raa, Rbb, and Rcc are as defined herein).
The term "unsaturated bond" refers to a double or triple bond.
The term "unsaturated" or "partially unsaturated" refers to a moiety that includes at least one double or triple bond.
The term "saturated" refers to a moiety that does not contain a double or triple bond, i.e., the moiety only contains single bonds.
As used herein, use of the phrase "at least one instance" refers to 1, 2, 3, 4, or more instances, but also encompasses a range, e.g., for example, from 1 to 4, from 1 to 3, from 1 to 2, from 2 to 4, from 2 to 3, or from 3 to 4 instances, inclusive.
A "non-hydrogen group" refers to any group that is defined for a particular variable that is not hydrogen.
These and other exemplary substituents are described in more detail in the Detailed ption, Examples, and claims. The invention is not intended to be limited in any manner by the above exemplary listing of substituents.
Other definitions The following tions are more general terms used throughout the present application.
As used , the term "salt" refers to any and all salts, and encompasses pharmaceutically acceptable salts.
The term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically able salts are well known in the art. For e, Berge et al. describe ceutically acceptable salts in detail in J. ceutical Sciences, 1977, 66, 1-19, incorporated herein by nce. Pharmaceutically WO 44620 acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids, such as hydrochloric acid, hydrobromic acid, oric acid, sulfuric acid, and perchloric acid or with organic acids, such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid or by using other methods known in the art such as ion exchange. Other ceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, rsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, sulfonate, formate, fumarate, glucoheptonate, ophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate , lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, enesulfonate, undecanoate, valerate salts, and the like. Salts derived from riate bases include alkali metal, alkaline earth metal, ammonium, and N+(Ci_4 alkyl)^ salts. Representative alkali or alkaline earth metal salts include sodium, m, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts e, when riate, nontoxic um, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, e, phosphate, e, lower alkyl sulfonate, and aryl sulfonate.
The term "solvate" refers to forms of the compound, or a salt thereof, that are ated with a solvent, usually by a solvolysis reaction. This al association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THE, diethyl ether, and the like. The compounds described herein may be prepared, e.g., in crystalline form, and may be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In certain instances, the solvate will be capable of isolation, for example, when one or more solvent molecules are incorporated in the crystal e of a crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates, and methanolates.
WO 44620 The term "hydrate" refers to a compound that is associated with water. Typically, the number of the water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, a hydrate of a compound may be ented, for e, by the general formula R x H2O, wherein R is the compound, and x is a number greater than 0. A given compound may form more than one type of hydrate, including, e.g., drates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, e.g., hemihydrates (R-0.5 H2O)), and drates (x is a number greater than 1, e.g., dihydrates (R-2 H2O) and hexahydrates (R-6 H2O)).
The term mers" or "tautomeric" refers to two or more interconvertible compounds resulting from at least one formal ion of a hydrogen atom and at least one change in valency (e.g., a single bond to a double bond, a triple bond to a single bond, or vice versa). The exact ratio of the ers depends on several factors, including temperature, solvent, and pH. Tautomerizations (i.e., the reaction providing a tautomeric pair) may catalyzed by acid or base. Exemplary tautomerizations include keto-to-enol, to-imide, lactam-tolactim , enamine-to-imine, and enamine-to-(a different enamine) tautomerizations.
It is also to be understood that compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed "isomers". Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers".
Stereoisomers that are not mirror images of one another are termed "diastereomers" and those that are non-superimposable mirror images of each other are termed "enantiomers". When a nd has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is le. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a "racemic mixture".
] The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof). All polymorphs have the same elemental composition. Different crystalline forms usually have different X-ray diffraction patterns, ed spectra, g points, density, hardness, crystal shape, optical and electrical properties, stability, and solubility.
Recrystallization solvent, rate of llization, storage temperature, and other factors may cause one crystal form to dominate. Various polymorphs of a compound can be prepared by crystallization under ent conditions.
The term "prodrugs" refers to compounds that have cleavable groups and become by solvolysis or under physiological conditions the compounds described herein, which are pharmaceutically active in vivo. Such examples include, but are not d to, choline ester derivatives and the like, N-alkylmorpholine esters and the like. Other derivatives of the compounds described herein have activity in both their acid and acid tive forms, but in the acid sensitive form often offer advantages of solubility, tissue compatibility, or delayed release in the mammalian organism (see, rd, H., Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid tives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acid with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a tuted or unsubstituted amine, or acid anhydrides, or mixed anhydrides. Simple aliphatic or aromatic esters, amides, and anhydrides derived from acidic groups pendant on the compounds described herein are ular prodrugs. In some cases it is desirable to prepare double ester type gs such as (acyloxy)alkyl esters or ((alkoxycarbonyl)oxy)alkylesters. Ci-g alkyl, C2-8 alkenyl, C2-8 alkynyl, aryl, €7.12 substituted aryl, and €7.12 arylalkyl esters of the compounds bed herein may be preferred.
The terms "composition" and "formulation" are used interchangeably.
A "subject" to which administration is contemplated refers to a human (/.
In certain embodiments, the plant is a ated plant. In n embodiments, the plant is a dicot. In n embodiments, the plant is a t. In certain embodiments, the plant is a flowering plant. In some embodiments, the plant is a cereal plant, e.g., maize, corn, wheat, rice, oat, barley, rye, or millet. In some embodiments, the plant is a legume, e.g., a bean plant, e.g., soybean plant. In some embodiments, the plant is a tree or shrub.
The term "biological sample" refers to any sample including tissue samples (such as tissue sections and needle biopsies of a tissue); cell samples (e.g., cytological smears (such as Pap or blood smears) or samples of cells obtained by microdissection); samples of whole organisms (such as samples of yeasts or bacteria); or cell fractions, fragments or organelles (such as obtained by lysing cells and ting the components thereof by centrifugation or otherwise). Other es of biological samples include blood, serum, urine, semen, fecal matter, cerebrospinal fluid, interstitial fluid, mucous, tears, sweat, pus, biopsied tissue (e.g., obtained by a surgical biopsy or needle biopsy), nipple aspirates, milk, vaginal fluid, , swabs (such as buccal swabs), or any material containing biomolecules that is derived from a first biological sample.
The term "target tissue" refers to any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is the object to which a compound, particle, and/or composition of the invention is red. A target tissue may be an al or thy tissue, which may need to be treated. A target tissue may also be a normal or healthy tissue that is under a higher than normal risk of becoming abnormal or unhealthy, which may need to be prevented. In certain embodiments, the target tissue is the liver. In n embodiments, the target tissue is the lung. A "non-target tissue" is any biological tissue of a subject (including a group of cells, a body part, or an organ) or a part thereof, including blood and/or lymph vessels, which is not a target tissue.
The term "administer," "administering," or "administration" refers to implanting, absorbing, ingesting, injecting, ng, or otherwise introducing a compound described herein, or a composition thereof, in or on a subject.
The terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease described herein. In some embodiments, treatment may be administered after one or more signs or symptoms of the disease have developed or have been observed. In other embodiments, treatment may be administered in the absence of signs or symptoms of the disease. For example, treatment may be administered to a susceptible subject prior to the onset of symptoms {e.g., in light of a y of symptoms).
Treatment may also be continued after ms have resolved, for example, to delay or prevent recurrence.
The terms "condition," "disease," and der" are used interchangeably.
] An "effective amount" of a compound described herein refers to an amount ient to elicit the desired biological response. An effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the cokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. In certain ments, an effective amount is a prophylactic ent. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amounts of a compound described herein in multiple doses.
A "therapeutically effective amount" of a compound described herein is an amount sufficient to provide a therapeutic benefit in the treatment of a condition or to delay or minimize one or more symptoms associated with the condition. A therapeutically effective amount of a compound means an amount of eutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces, or avoids ms, signs, or causes of the ion, and/or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically ive amount is an amount sufficient for fibrosis inhibition. In certain embodiments, a therapeutically effective amount is an amount sufficient for treating diseases associated with fibrosis. In certain embodiments, a therapeutically effective amount is an amount sufficient for fibrosis inhibition and treating diseases associated with fibrosis.
A "prophylactically effective amount" of a nd described herein is an amount sufficient to t a condition, or one or more signs or symptoms associated with the condition, or prevent its recurrence. A lactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the condition. The term "prophylactically effective amount" can encompass an amount that improves l laxis or enhances the prophylactic efficacy of another prophylactic agent. In certain ments, a prophylactically effective amount is an amount sufficient for fibrosis inhibition. In certain embodiments, a prophylactically effective amount is an amount sufficient for treating es associated with is. In certain embodiments, a prophylactically effective amount is an amount sufficient for fibrosis inhibition and treating diseases associated with fibrosis.
As used herein, the term "inhibit" or "inhibition" in the context of the TGF-P signalling pathway, for example, refers to a reduction in the activity of TGF-P or another enzyme in the TGF-P signalling pathway (e.g., ERK), a reduction in the ty of TGF-P induced proline incorporation in cells, and/or a reduction in the activity of TGF-P induced ellular matrix production. In some embodiments, the term refers to a reduction of the level of enzyme activity (e.g., TGF-P activity), a reduction in the activity of TGF-P induced proline incorporation in cells, and/or a reduction in the activity of TGF-P induced extracellular matrix production, to a level that is tically significantly lower than an initial level, which may, for example, be a baseline level of enzyme activity. In some embodiments, the term refers to a reduction of the level of enzyme activity (e.g., TGF-P activity), a reduction in the activity of TGF-P induced proline oration in cells, and/or a reduction in the activity of TGF-P induced extracellular matrix production, to a level that is less than 75%, less than 50%, less than 40%, less than 30%, less than 25%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, less than 0.5%, less than 0.1%, less than 0.01%, less than 0.001%, or less than 0.0001% of an initial level, which may, for example, be a baseline level of enzyme activity.
The term "benign or malignant neoplastic disease" as used herein refers to any growth or tumour caused by abnormal and uncontrolled cell division. In certain embodiments, the malignant neoplastic e may be cancer.
The term "cancer" refers to a malignant neoplasm (Stedman ’s Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins: Philadelphia, 1990). Exemplary cancers include, but are not limited to, acoustic a; adenocarcinoma; adrenal gland cancer; anal cancer; angiosarcoma (e.g., ngiosarcoma, ngioendotheliosarcoma, hemangiosarcoma); ix cancer; benign onal gammopathy; biliary cancer (e.g., giocarcinoma); bladder ; breast cancer (e.g., adenocarcinoma of the breast, ary carcinoma of the breast, mammary cancer, medullary carcinoma of the breast); brain cancer (e.g.,meningioma, glioblastomas, glioma (e.g., astrocytoma, oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid tumor; cervical cancer (e.g., cervical adenocarcinoma); choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer (e.g., colon cancer, rectal cancer, colorectal adenocarcinoma); connective tissue cancer; epithelial carcinoma; ependymoma; endotheliosarcoma (e.g., Kaposi’s sarcoma, multiple thic hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer, e sarcoma); esophageal cancer (e.g., adenocarcinoma of the esophagus, Barrett’s adenocarcinoma); Ewing’s sarcoma; eye cancer (e.g., intraocular melanoma, retinoblastoma); familiar hypereosinophilia; gall bladder cancer; gastric cancer (e.g., h adenocarcinoma); gastrointestinal stromal tumor (GIST); germ cell cancer; head and neck cancer (e.g., head and neck squamous cell carcinoma, oral cancer (e.g., oral squamous cell carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal , nasopharyngeal cancer, oropharyngeal cancer)); hematological cancers (e.g., leukemia such as acute cytic leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL)); lymphoma such as Hodgkin ma (HL) (e.g., B-cell HL, T-cell HL) and non-Hodgkin ma (NHL) (e.g., diffuse large B-cell lymphoma (DLBCL)), follicular lymphoma, c lymphocytic leukemia/small lymphocytic lymphoma LL), mantle cell lymphoma (MCL), marginal zone B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT) lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal zone B-cell lymphoma), y mediastinal B-cell lymphoma, Burkitt lymphoma, lymphoplasmacytic lymphoma (i.e., strom’s macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma and primary central nervous system (CNS) lymphoma; and T-cell NHL such as precursor T-lymphoblastic lymphoma/leukemia, peripheral T-cell lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g., mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell lymphoma, extranodal l killer T-cell lymphoma, enteropathy type T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, and anaplastic large cell lymphoma); a mixture of one or more leukemia/lymphoma as described above; and multiple myeloma ), heavy chain disease (e.g., alpha chain disease, gamma chain disease, mu chain e); hemangioblastoma; hypopharynx cancer; inflammatory myofibroblastic tumors; immunocytic amyloidosis; kidney cancer (e.g., nephroblastoma a.k.a.
Wilms’ tumor, renal cell carcinoma); liver cancer (e.g., hepatocellular cancer (HCC), malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma,small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis (e.g., systemic mastocytosis); muscle cancer; myelodysplastic syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD) (e.g., polycythemia vera (PV), essential thrombocytosis (ET), agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (ME), chronic idiopathic myelofibrosis, c myelocytic leukemia (CML), chronic neutrophilic ia (CNL), hypereosinophilic me (HES)); lastoma; neurofibroma (e.g., neurofibromatosis (NF) type 1 or type 2, schwannomatosis); neuroendocrine cancer (e.g., gastroenteropancreatic neuroendocrine tumor ET), carcinoid tumor); osteosarcoma (e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma, n embryonal carcinoma, n adenocarcinoma); papillary arcinoma; pancreatic cancer (e.g., pancreatic andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN), Islet cell ); penile cancer (e.g., s disease of the penis and scrotum); oma; primitive neuroectodermal tumor (PNT); plasma cell neoplasia; paraneoplastic syndromes; intraepithelial neoplasms; prostate cancer (e.g., prostate adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland cancer; skin cancer (e.g., squamous cell carcinoma (SCC), keratoacanthoma (KA), melanoma, basal cell oma (BCC)); small bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g., malignant fibrous histiocytoma (MFH), liposarcoma, malignant peripheral nerve sheath tumor (MPNST), chondrosarcoma, fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small intestine cancer; sweat gland carcinoma; synovioma; testicular cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid carcinoma (PTC), medullary thyroid cancer); urethral cancer; vaginal cancer; and vulvar cancer (e.g., Paget’s disease of the vulva).
The term "immunotherapy" refers to a therapeutic agent that promotes the ent of disease by inducing, enhancing, or suppressing an immune response. Immunotherapies designed to elicit or amplify an immune response are classified as activation therapies, while therapies that reduce or suppress are classified as suppression immunotherapies.
Immunotherapies are typically, but not always, biotherapeutic agents. Numerous immunotherapies are used to treat . These include, but are not limited to, monoclonal antibodies, adoptive cell transfer, cytokines, chemokines, vaccines, and small molecule inhibitors.
] The term "small molecule" or "small molecule therapeutic" refers to molecules, whether naturally occurring or artificially created (e.g., via al synthesis) that have a relatively low molecular weight. Typically, a small molecule is an organic compound (i.e., it contains ). The small molecule may contain multiple carbon-carbon bonds, stereocenters, and other functional groups (e.g., amines, yl, carbonyls, and heterocyclic rings, etc.). In n embodiments, the molecular weight of a small molecule is not more than about 1,000 g/mol, not more than about 900 g/mol, not more than about 800 g/mol, not more than about 700 g/mol, not more than about 600 g/mol, not more than about 500 g/mol, not more than about 400 g/mol, not more than about 300 g/mol, not more than about 200 g/mol, or not more than about 100 g/mol. In certain embodiments, the molecular weight of a small molecule is at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, or at least about 900 g/mol, or at least about 1,000 g/mol. Combinations of the above ranges (e.g., at least about 200 g/mol and not more than about 500 g/mol) are also possible. In certain embodiments, the small molecule is a therapeutically active agent such as a drug (e.g., a molecule approved by the U.S. Food and Drug Administration as provided in the Code of l Regulations (C.F.R.)). The small molecule may also be xed with one or more metal atoms and/or metal ions. In this instance, the small molecule is also referred to as a "small organometallic molecule." Preferred small molecules are biologically active in that they produce a biological effect in animals, preferably mammals, more ably humans. Small molecules include, but are not limited to, radionuclides and imaging agents. In certain embodiments, the small molecule is a drug. Preferably, though not necessarily, the drug is one that has already been deemed safe and effective for use in humans or animals by the appropriate governmental agency or tory body. For example, drugs approved for human use are listed by the FDA under 21 C.F.R. §§ 330.5, 331 through 361, and 440 through 460, incorporated herein by reference; drugs for veterinary use are listed by the FDA under 21 C.F.R. §§ 500 through 589, incorporated herein by reference. All listed drugs are considered acceptable for use in accordance with the present invention.
The term "therapeutic agent" refers to any substance having therapeutic properties that e a desired, usually cial, effect. For example, therapeutic agents may treat, ameliorate, and/or prevent disease. Therapeutic agents, as disclosed herein, may be biologies or small molecule therapeutics.
The term "chemotherapeutic agent" refers to a therapeutic agent known to be of use in chemotherapy for cancer.
The term "kidney disease", as used herein, may refer to a disorder of at least one kidney in a subject that mises the function of the kidney. The kidney disease may result from a primary pathology of the kidney (e.g., injury to the glomerulus or tubule), or another organ (e.g., pancreas) which adversely s the ability of the kidney to perform biological functions. A kidney disease in the human can be the direct or indirect effect of disease. Examples of a kidney disease as a result or consequence of an indirect effect on the kidneys is kidney disease as a consequence of es or ic lupus. A kidney disease may be the result or a consequence of any change, damage, or trauma to the glomerulus, s or interstitial tissue in either the renal cortex or renal medulla of the kidney.
The term "kidney disease", as used herein, may refer to a progressive kidney disease that over time (e.g., days, weeks, months, years) leads to a loss of renal function.
The kidney disease may include, but is not limited to, a progressive glomerular kidney disease including, without tion, diabetic nephropathy (e.g., as a consequence of Type I or Type II diabetes or systemic lupus), primary glomerulonephritis (e.g., nous nephropathy, focal segmental glomerulosclerosis, membranoproliferative ulonephritis, diffuse proliferative glomerulonephritis, membranous focal tal ulosclerosis) or secondary glomerulonephritis (e.g., diabetic nephropathy, ischemic nephropathy).
The term "renal function", as used , refers to a logical property of the kidney, such as the ability to retain protein thereby preventing proteinuria. Renal function can be assessed using methods known in the art such as determining one or more of glomerular filtration rate (e.g., creatinine clearance), excretion of protein in urine, blood urea nitrogen, and serum or plasma creatinine.
A progressive kidney disease treated by the itions and methods bed herein includes any kidney disease that can, ultimately, lead to end-stage renal disease. A progressive kidney disease that can be treated by the compositions and s of the invention can be, for example, associated with endogenous iron deposit in the kidney (e.g., glomerulus, tubules).
"Diabetic cardiomyopathy" refers to any one or more cardiac pathology and/or ction in a subject, which is a complication of either Type I or Type II diabetes in the subject. The diabetes may be symptomatic or asymptomatic. Cardiac pathology which is characteristic of ic cardiomyopathy includes myocellular hypertrophy, myocardial fibrosis, and in some cases left ventricular hypertrophy. The pathologies which are plated arise independently from complications arising from coronary artery disease, although both ic complications and ry artery complications may be present in the same subject. lic dysfunction, such as an impairment in early diastolic filling, a prolongation of isovolumetric relaxation and increased atrial g is also characteristic of diabetic cardiomyopathy, and may be identified using Doppler methods such as Doppler 2-dimensional echocardiography (for e Redford MM et al., "Burden of systolic and lic dysfunction in the community".
JAMA (2003) 289:194-203) or radionuclide imaging for early or mild dysfunction and by standard echocardiograph testing for more severe dysfunction.
"Cardiac fibrosis" refers to the formation of fibrous tissue, including cellular and extracellular components, in the lining and muscle of the heart. If present in sufficient quantities, the fibrous tissue will result in a decrease in the contractility and/or relaxation of one or more regions of the heart, ing in functional t in cardiac output.
Detailed ption of Certain Embodiments Provided herein are anti-fibrotic compounds. The compounds may inhibit fibrosis. The compounds may inhibit the TGF-P signalling pathway. The compounds may inhibit TGF-P, or another enzyme in the TGF-P ling pathway (e.g., ERK). The compounds may inhibit TGF- P induced proline incorporation in cells. The compounds may inhibit TGF-P induced extracellular matrix production. The compounds may inhibit collage biosynthesis. In one , the disclosure provides compounds of Formula I, and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, stereoisomers, isotopically labeled derivatives, prodrugs, and ceutical compositions thereof. In another aspect, the disclosure provides 2- 3-[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid, and ceutically acceptable salts, solvates, hydrates, polymorphs, co-crystals, tautomers, isomers, isotopically d derivatives, prodrugs, and pharmaceutical compositions thereof. The compounds are useful for the treatment and/or prevention of diseases or conditions ated with is (e.g., kidney disease, cardiac e), inflammation, and/or a benign or malignant neoplastic disease in a subject in need thereof.
Compounds ] The compounds described herein interact with the TGF-P signalling pathway. As described herein, the therapeutic effect may be a result of inhibition of TGF-P or another enzyme in the TGF-P signalling pathway {e.g., ERK). A compound may be provided for use in any composition, kit, or method described herein as a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug thereof.
In one aspect, disclosed is a compound of Formula I: Z'R XT^N (R6)m R2-Y- or a pharmaceutically acceptable salt thereof; wherein R4 a R5 Tis R5 or X is O, NR10, -NR10C(O)-, or a bond; Y is O, NR10, -C(0)NR10-, or a bond; Z is O, NR10, or a bond; R and R are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or cyclylalkyl, wherein R and R1 2 are each optionally substituted with 1-3 independent substituents R ;o or R and R together with the atoms to which they are attached form a heterocyclyl ring;1 2 R is en, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, a heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R3 is optionally substituted with 1-3 independent substituents R ;o R4 and R5 are hydrogen; each occurrence of R6 is, independently, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, alkoxy, aryl, heteroaryl, cyclyl, NRaRb, or -S(0)2RC; G is C(0)R7 or en; R7is OH or NHR9; m is 0, 1, or 2; each occurrence of R is, ndently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, o aryl, heteroaryl, cyclyl, -NRaRb, -S(0)2RC, or -C02Rd; R9is heteroaryl, heterocyclyl, or -S(0)2RC, wherein R9is ally substituted with 1-3 independent tuents R ;o R is hydrogen or alkyl optionally substituted with 1-3 independent substituents R ; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)0Ci_6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring; provided that when G is hydrogen, then m is not 0; provided that when G is C(0)R7, R7 is OH, and -Z-R3 is H, then at least one of -X-R1 and-Y-R is-O-heterocyclyl or heterocyclyl, or R and R together with the atoms to which they are attached form a heterocyclyl ring; provided that when -X-R1 is H, then neither -Y-R2 nor -Z-R3 are en; provided that when-Y-R is H, then neither-X-R nor-Z-R are hydrogen; and provided that when-Z-R is H, then neither-X-R nor-Y-R are hydrogen.3 12 In certain embodiments, AkKR4 Tis X is O, NR10, -NR10C(O)-, or a bond; Y is O, NR10, -C(0)NR10 or a bond; Z is O, NR10, or a bond; R1 and R2 are independently hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cyclyl, or cyclylalkyl, wherein R and R1 2 are each optionally tuted with 1-3 independent tuents R ;o or R and R together with the atoms to which they are attached form a heterocyclyl ring;1 2 R is en, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl,a heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3a independent substituents R ;o R4 and R5 are hydrogen; each occurrence of R6 is, independently, halogen, cyano, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyl, , aryl, heteroaryl, heterocyclyl, NRaRb, or -S(0)2RC; G is C(0)R7 or hydrogen; R7is OH or NHR9; m is 0 or 1; each occurrence of R is, ndently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, o aryl, heteroaryl, cyclyl, -NRaRb, -S(0)2RC, or -C02Rd; R9is heteroaryl, heterocyclyl, or -S(0)2RC, wherein R9is optionally substituted with 1-3 independent substituents R ;o R is en or alkyl optionally substituted with 1-3 independent substituents R ; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)0Ci_6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring; provided that when G is hydrogen, then m is not 0; provided that when G is C(0)R7, R7 is OH, and -Z-R3 is H, then at least one of -X-R1 and-Y-R is-O-heterocyclyl or cyclyl, or R and R together with the atoms to which they are attached form a heterocyclyl ring; provided that -R is H, then neither-Y-R nor-Z-R are hydrogen;1 2 3 provided that when-Y-R is H, then neither-X-R nor-Z-R are hydrogen; and2 13 provided that when-Z-R is H, then neither-X-R nor-Y-R are hydrogen.3 12 R4 a R5 In n embodiments, T is R5 . In certain embodiments, T is In certain embodiments, X is O, NR10, or a bond. In certain embodiments, X is O or a bond. In certain embodiments, X is O. In certain embodiments, X is a bond. In certain embodiments, Y is NR10. In n embodiments, X is -NR10C(O)-.
In certain embodiments, Y is O, NR10, or a bond. In n embodiments, Y is O or a bond. In certain embodiments, Y is O. In certain embodiments, Y is a bond. In certain embodiments, Y is NR10. In certain embodiments, Y is -NR10C(O)-.
In certain embodiments, Z is O or a bond. In certain ments, Z is O. In certain embodiments, Z is a bond. In certain embodiments, Z is NR10.
In certain embodiments, R1 is hydrogen, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, kyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .
In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with 1-3 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with an alkyl group.
In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is alkynyl. In certain embodiments, R1 is C2-4 alkynyl. In certain embodiments, R1 is lkylalkyl. In certain ments, R1 is cyclopropylmethyl. In certain embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or zinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is heterocyclylalkyl ally substituted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In certain ments, R is en, alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or cyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .
] In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, 2 arylalkyl, or heterocyclylalkyl, n R is optionally substituted with 1-3 independent substituents R .o In certain embodiments, R is alkyl, alkynyl, heterocyclyl, arylalkyl, or2 heterocyclylalkyl, n R is optionally substituted with an alkyl group.2 In certain embodiments, R is alkyl or heteroarylalkyl optionally substituted with an 2 alkyl group.
In certain embodiments, R is alkyl. In certain embodiments, R is Ci_4 alkyl. In certain2 2 embodiments, R is alkynyl. In certain embodiments, R is C2-4 alkynyl. In certain embodiments, 2 2 R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is morpholinyl or tetrahydopyridinyl, optionally tuted with an alkyl group. In certain embodiments, R is heterocyclylalkyl optionally substituted with an alkyl group. In n embodiments, R is heteroarylalkyl ally substituted with one or two alkyl groups. In certain ments, R is pyrazolylmethyl optionally substituted with one or two alkyl .
In certain embodiments, R and R together with the atoms to which they are attached form a heterocyclyl ring.
In certain embodiments, R is hydrogen, heteroalkyl, alkyl, alkynyl, heteroarylalkyl,a heterocyclyl, or heterocyclylalkyl, wherein R is ally substituted with 1-3 independenta substituents R .o In certain embodiments, R is en, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, a or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
In certain embodiments, R3 is alkyl optionally substituted with -NRaRb. In n embodiments, R is alkyl optionally substituted with -N(Me)2. In certain embodiments, R is C1-4 alkyl optionally substituted with -N(Me)2. In certain embodiments, R is l. In certaina embodiments, R is C2-4 alkynyl. In certain embodiments, R is heteroarylalkyl. In certain 3 3 embodiments, R is pyridinylmethyl. In certain ments, R is heterocyclyl. In certain embodiments, R is idinyl, piperidinyl, or azetidinyl. In certain embodiments, R is heterocyclylalkyl. In certain embodiments, R3 is linylethyl or morpholinylmethyl.
In certain embodiments, each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, cyclyl, or -S(0)2RC. In certain embodiments, each occurrence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In n ments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each occurrence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each occurrence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each occurrence of R6 is Ci_4 alkyl. In certain ments, each occurrence of R6is methyl. In certain embodiments, each occurrence of R6is heteroaryl. In certain embodiments, each ence of R6is triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, or imidazolyl. In certain embodiments, each occurrence of R6 is heterocyclyl. In certain embodiments, each occurrence of R6is dihydrooxadiazolyl or oxodihydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain embodiments, each occurrence of R6is Me.
In certain ments, G is C(0)R . In certain embodiments, G is hydrogen. n ] In certain embodiments, R is OH. In certain embodiments, R is NHR .
In certain embodiments, m is 0 or 1. In certain ments, m is 0 or 2. In certain embodiments, m is 1 or 2. In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.
In certain embodiments, R9 is heteroaryl, heterocyclyl, or -S(0)2RC. In certain embodiments, R9 is heteroaryl optionally substituted with up to two alkyl . In certain embodiments, R9 is tetrazolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, each of which is ally tuted with up to two alkyl groups. In certain embodiments, R9 is heterocyclyl optionally substituted with up to two alkyl groups. In certain embodiments, R9 is oxetanyl or piperidinyl, each of which is optionally substituted with up to two alkyl groups. In certain embodiments, R9 is -S(0)2RC. In certain embodiments, R9 is -S(0)2Me.
In certain embodiments, R10 is en or alkyl. In certain embodiments, R10 is hydrogen. In certain embodiments, R10is Ci_4 alkyl. In n embodiments, R10is methyl.
In certain embodiments, the compound of Formula I is of Formula I-a: Z'R XT^N (R6)m R2-Y- or a pharmaceutically acceptable salt thereof.
In certain ments, the compound of Formula I is of Formula I-b or Formula I-c: Z-R3 O Z-R3 X(R6)m O (R6)m R2-Y- r2-y- N N H H R-X R-X I-b, I-c, or a pharmaceutically acceptable salt thereof.
WO 44620 In n embodiments, X is O or a bond; Y is O or a bond; Z is O or a bond; R and R2 are independently hydrogen, alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R and R are each optionally substituted with 1 or 2 independent substituents R ;or R and R together with the atoms to which they are attached form a8 1 2 heterocyclyl ring; R is en, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or a heterocyclylalkyl, wherein R is optionally substituted with 1 or 2 independent substituents R ; each occurrence of R6 is, independently, halogen, cyano, alkyl, aryl, heterocyclyl, or - S(0)2Rc; m is 1 or 2; each occurrence of R8 is, independently, alkyl or NRaRb; and each ence of Ra, Rb, and Rc is, independently, en, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and heterocyclyl.
In certain embodiments, X is O. In certain embodiments, X is a bond.
In n ments, Y is O. In certain embodiments, Y is a bond.
] In certain embodiments, Z is O. In certain embodiments, Z is a bond.
In certain embodiments, R1 is hydrogen, alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally tuted with 1 or 2 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1 or 2 independent substituents R .
] In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with an alkyl group.
In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is alkynyl. In certain embodiments, R1 is C2-4 alkynyl. In n embodiments, R1 is cycloalkylalkyl. In certain embodiments, R1 is cyclopropylmethyl. In certain embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, linyl, or piperazinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In certain embodiments, R is hydrogen, alkyl, alkynyl, cycloalkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is ally substituted with 1 or2 2 independent substituents R .o ] In certain embodiments, R is alkyl, alkynyl, arylalkyl, heterocyclyl, or 2 cyclylalkyl, wherein R2 is optionally tuted with 1 or 2 independent substituents R8.
In certain embodiments, R is alkyl, alkynyl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl, wherein R is optionally substituted with an alkyl group.2 ] In certain embodiments, R is alkyl or heteroarylalkyl optionally substituted with an alkyl group.
In certain embodiments, R is alkyl. In certain embodiments, R is Ci_4 alkyl. In certain embodiments, R is alkynyl. In certain embodiments, R is C2-4 alkynyl. In certain embodiments, 2 2 R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is linyl or tetrahydopyridinyl, ally substituted with an alkyl group. In certain ments, R is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is heteroarylalkyl optionally substituted with one or two alkyl groups. In certain embodiments, R is pyrazolylmethyl optionally substituted with one or two alkyl groups.
] In certain embodiments, R and R together with the atoms to which they are attached form a heterocyclyl ring.
In certain embodiments, R is hydrogen, alkyl, l, heteroarylalkyl, heterocyclyl,a or cyclylalkyl, wherein R is optionally substituted with 1 or 2 independent substituents R .3 8 In certain embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, a or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
In certain ments, R3 is alkyl optionally substituted with -NRaRb. In certain embodiments, R is alkyl optionally substituted with -N(Me)2. In certain embodiments, R is C1-4 alkyl optionally substituted with -N(Me)2. In n embodiments, R is alkynyl. In n a embodiments, R3is C2-4 alkynyl. In certain embodiments, R3is heteroarylalkyl. In certain embodiments, R is pyridinylmethyl. In n embodiments, R is heterocyclyl. In certain embodiments, R is pyrrolidinyl, piperidinyl, or azetidinyl. In certain embodiments, R is3 3 heterocyclylalkyl. In certain embodiments, R is morpholinylethyl or morpholinylmethyl.a In certain embodiments, each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC. In certain embodiments, each occurrence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain embodiments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each occurrence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each occurrence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each occurrence of R6 is Ci_4 alkyl. In certain embodiments, each occurrence of R6is . In certain ments, each occurrence of R6is heteroaryl. In n embodiments, each occurrence of R6is lyl, tetrazolyl, oxadiazolyl, pyrazolyl, or imidazolyl. In certain ments, each occurrence of R6 is heterocyclyl. In certain embodiments, each occurrence of R6is ooxadiazolyl or oxodihydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain embodiments, each occurrence of R6is -S(0)2Me.
In certain ments, m is 1. In certain embodiments, m is 2.
In certain embodiments, the compound of Formula I-b is of Formula I-b-1: Z-R3 O R2-Y> I-b-1, or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In n embodiments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the compound of Formula I-c is of a I-c-1: Z-R3 O I-c-1, or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain embodiments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the compound of Formula I is of Formula I-d or Formula I-e: O O (R6)m (R6)m R2-Y- r2-y- N N H H R-X R-X Id, I-e, or a pharmaceutically acceptable salt thereof.
In n embodiments, X is O or a bond;Y is O or a bond; provided that at least one of X and Y is O; R and R are independently, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein said heteroarylalkyl, heterocyclyl, and heterocyclylalkyl are optionally substituted with 1 or 2 independent alkyl groups; each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC; m is 1 or 2; and each occurrence of Rc is alkyl.
In certain ments, X is O. In certain embodiments, X is a bond.
In certain embodiments, Y is O. In certain embodiments, Y is a bond.
In certain embodiments, R1 is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein said heteroarylalkyl, cyclyl, and heterocyclylalkyl are optionally substituted with 1 or 2 independent alkyl groups.
In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is alkynyl. In n embodiments, R1 is C2-4 alkynyl. In certain embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In n ments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or piperazinyl, optionally substituted with an alkyl group. In certain embodiments, R1 is cyclylalkyl optionally tuted with an alkyl group. In certain ments, R1 is oxetanylmethyl.
In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .2 8 In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, cyclyl, heteroarylalkyl, or heterocyclylalkyl, wherein said heteroarylalkyl, cyclyl, and heterocyclylalkyl are optionally substituted with 1 or 2 independent alkyl groups.
In certain embodiments, R is alkyl or heteroarylalkyl ally substituted with an alkyl group.
In certain embodiments, R is alkyl. In certain embodiments, R is Ci_4 alkyl. In certain embodiments, R is l. In certain ments, R is C2-4 alkynyl. In certain embodiments, 2 2 R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is morpholinyl or tetrahydopyridinyl, optionally substituted with an alkyl group. In certain embodiments, R is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is heteroarylalkyl optionally substituted with one or two alkyl groups. In 2 certain ments, R2 is lylmethyl optionally substituted with one or two alkyl groups.
In certain embodiments, R and R together with the atoms to which they are attached form a heterocyclyl ring.
In certain ments, each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC. In certain embodiments, each occurrence of R6is n. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain embodiments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain ments, each occurrence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain ments, each occurrence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each ence of R6 is Ci_4 alkyl. In certain embodiments, each occurrence of R6is methyl. In certain ments, each occurrence of R6is heteroaryl. In certain embodiments, each occurrence of R6is triazolyl, olyl, oxadiazolyl, pyrazolyl, or imidazolyl. In certain embodiments, each occurrence of R6 is heterocyclyl. In certain embodiments, each occurrence of R6is dihydrooxadiazolyl or oxodihydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain embodiments, each occurrence of R6is -S(0)2Me.
In certain embodiments, m is 1. In certain embodiments, m is 2.
In certain ments, the compound of Formula I-d is of Formula I-d-1: R2-Y> I-d-1, or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain ments, R6is F, Cl, or cyano. In n embodiments, R6is F or cyano. In certain embodiments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the compound of Formula I-e is of Formula I-e-1: R2-Y> I-e-1, or a pharmaceutically acceptable salt f.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain embodiments, R6is F. In certain embodiments, R6is cyano.
In certain embodiments, the compound of a I is of Formula I-f: OR3 O (R6)m H G or a pharmaceutically acceptable salt thereof; wherein G is CO2H or hydrogen; W is CN or hydrogen; m is 0 or 1; provided that when G is CO2H, then W is hydrogen; and when W is CN, then G is hydrogen; and provided that when G and W are both hydrogen, then m is 1.
In certain embodiments, R and R are independently alkyl, alkenyl, alkynyl, 1 2 cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, cyclyl, or cyclylalkyl, wherein R and R are each optionally substituted with 1-3 independent substituents R ; or R and R together with the atoms to which they are attached form a heterocyclyl ring; R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituted with 1-3 ndent substituents R ; R is halogen, cyano, alkyl, haloalkyl, hydroxyl, alkoxy, yl, aryl, heteroaryl, heterocyclyl, - (CH2)nC(0)NRaRb, -S(0)2Rc, or NRaRb; m is 0 or 1; q is 0 or 1; n is 0 or 1; and m + n + q is 1 or 2; provided that when n is 1, then q is 0; and when q is 1, then n is 0.
In certain embodiments, R1 is alkyl, alkenyl, l, cycloalkyl, cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is ally substituted with 1-3 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, lkylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R1 is optionally substituted with 1-3 independent substituents R .o In certain embodiments, R1 is alkyl, alkynyl, cycloalkylalkyl, cyclyl, or heterocyclylalkyl, n R1 is optionally substituted with an alkyl group.
In certain embodiments, R1 is alkyl. In certain embodiments, R1 is C1-4 alkyl. In certain embodiments, R1 is alkynyl. In certain embodiments, R1 is C2-4 l. In certain embodiments, R1 is cycloalkylalkyl. In certain embodiments, R1 is cyclopropylmethyl. In certain embodiments, R1 is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R1 is pyrrolidinyl, tetrahydropyridinyl, morpholinyl, or piperazinyl, optionally tuted with an alkyl group. In certain embodiments, R1 is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R1 is oxetanylmethyl.
In n embodiments, R is alkyl, alkenyl, alkynyl, cycloalkyl, lkylalkyl, kyl, heteroarylalkyl, heterocyclyl, or cyclylalkyl, wherein R and R are each1 2 optionally substituted with 1-3 independent substituents R .o In certain embodiments, R is alkyl, alkynyl, heteroarylalkyl, heterocyclyl, 2 heteroarylalkyl, or heterocyclylalkyl, wherein R is ally tuted with 1-3 independent substituents R .o In n embodiments, R is alkyl, alkynyl, heterocyclyl, heteroarylalkyl, or2 heterocyclylalkyl, wherein R is optionally substituted with an alkyl group.2 In certain embodiments, R is alkyl or heteroarylalkyl optionally substituted with an alkyl group.
In certain embodiments, R2 is alkyl. In certain embodiments, R2 is Ci_4 alkyl. In certain embodiments, R is alkynyl. In certain ments, R is C2-4 alkynyl. In certain embodiments, R is heterocyclyl optionally substituted with an alkyl group. In certain embodiments, R is morpholinyl or tetrahydopyridinyl, optionally substituted with an alkyl group. In certain embodiments, R is heterocyclylalkyl optionally substituted with an alkyl group. In certain embodiments, R is heteroarylalkyl optionally tuted with one or two alkyl groups. In certain embodiments, R is pyrazolylmethyl optionally substituted with one or two alkyl groups.
] In certain embodiments, R and R together with the atoms to which they are attached 1 2 form a heterocyclyl ring.
In certain embodiments, R and R are independently alkyl, alkynyl, or1 2 lkylalkyl. In certain embodiments, R and R are alkyl. In certain embodiments, R and R12 12 are Ci-4 alkyl.
In certain embodiments, R is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl,a arylalkyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally substituteda with 1-3 independent substituents R .o In certain embodiments, R is alkyl, heteroalkyl, heterocyclyl, heteroarylalkyl, ora heterocyclylalkyl, wherein R is optionally substituted with 1-3 independent substituents R .3 8 In n embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, a or heterocyclylalkyl, wherein R3 is optionally substituted with -NRaRb or alkyl.
In certain ments, R3 is alkyl substituted with NRaRb, cyclyl substituted with alkyl, unsubstituted heterocyclyl, unsubstituted heteroarylalkyl, or unsubstituted heterocyclylalkyl.
In certain embodiments, R3 is Ci_4 alkyl substituted with NRaRb; wherein each occurrence of Ra and Rb is alkyl.
In certain embodiments, R3 is alkyl optionally tuted with -NRaRb. In certain embodiments, R is alkyl optionally substituted with -N(Me)2. In certain ments, R is Ci_4 alkyl ally substituted with -N(Me)2. In certain embodiments, R is alkynyl. In certaina embodiments, R is C2-4 alkynyl. In certain embodiments, R is heteroarylalkyl. In certain 3 3 embodiments, R is nylmethyl. In certain embodiments, R is heterocyclyl. In certain embodiments, R3 is idinyl, piperidinyl, or azetidinyl. In certain embodiments, R3 is heterocyclylalkyl. In n embodiments, R is morpholinylethyl or morpholinylmethyl.a In n embodiments, each occurrence of R6 is, independently, halogen, cyano, alkyl, heteroaryl, heterocyclyl, or -S(0)2RC. In n embodiments, each occurrence of R6is halogen. In certain embodiments, each occurrence of R6 is F, Cl, Br, or I. In certain embodiments, each occurrence of R6 is F, Cl, or Br. In certain embodiments, each occurrence of R6 is F. In certain embodiments, each occurrence of R6 is Cl. In certain embodiments, each occurrence of R6 is Br. In certain embodiments, each occurrence of R6 is cyano. In certain embodiments, each occurrence of R6 is alkyl. In certain embodiments, each occurrence of R6 is C1-4 alkyl. In certain embodiments, each occurrence of R6is methyl. In certain embodiments, each occurrence of R6is heteroaryl. In certain embodiments, each occurrence of R6is triazolyl, tetrazolyl, oxadiazolyl, pyrazolyl, or imidazolyl. In certain embodiments, each occurrence of R6 is heterocyclyl. In certain ments, each occurrence of R6is dihydrooxadiazolyl or oxodihydrooxadiazolyl. In certain embodiments, each occurrence of R6is -S(0)2RC. In certain embodiments, each occurrence of R6is -S(0)2Me.
In certain ments, G is CO2H. In certain embodiments, G is hydrogen.
In certain embodiments, W is CN. In certain embodiments, W is hydrogen.
In certain embodiments, m is 0. In certain embodiments, m is 1.
In certain embodiments, the compound of Formula I is of Formula I-g: OR3 O or a pharmaceutically acceptable salt thereof.
In certain embodiments, R6is F, Cl, Br, or cyano. In certain embodiments, R6is F, Cl, or cyano. In certain embodiments, R6is F or cyano. In certain embodiments, R6is F. In certain embodiments, R6is cyano.
] In n embodiments, the nd of Formula I is a compound of Formula I-h: OR3 O or a pharmaceutically acceptable salt thereof.
In certain embodiments, R is en, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R is optionally tuted with 1-3 independent substituents R .3 8 In certain embodiments, R is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R3 is optionally tuted with -NRaRb or alkyl.
In certain embodiments, R3 is alkyl optionally substituted with -NRaRb. In n embodiments, R3 is C1-4 alkyl substituted with NRaRb; n each occurrence of Ra and Rb is alkyl. In n embodiments, R is alkyl optionally substituted with -N(Me)2. In certain ments, R is C1-4 alkyl optionally substituted with -N(Me)2. In certain embodiments, R is 3 3 ethyl tuted with NRaRb; wherein each occurrence of Ra and Rb is C1-4 alkyl. In certain embodiments, R3 is ethyl substituted with NRaRb; wherein each occurrence of Ra and Rb is methyl, ethyl, or propyl. In certain embodiments, R3 is ethyl substituted with NRaRb; wherein each occurrence of Ra and Rb is methyl. In certain embodiments, R3 is alkynyl. In certain embodiments, R is C2-4 alkynyl. In certain embodiments, R is heteroarylalkyl. In certain embodiments, R is pyridinylmethyl. In certain embodiments, R is cyclyl. In certain3 3 embodiments, R is pyrrolidinyl, piperidinyl, or azetidinyl. In n ments, R is3 3 heterocyclylalkyl. In certain embodiments, R is morpholinylethyl or morpholinylmethyl.a In certain embodiments, the nd of a I is a compound of the formula: O O or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula I is a compound of the formula I-i: R9 ,Y- N ph 7\R H / x co2h or a pharmaceutically acceptable salt thereof.
In certain embodiments, X is O, NR10, -NR10C(O)-, or CRllaRllb; Y is O, NR10, - C(0)NR10-, or CRllaRllb; provided that at least one of X and Y is not CRllaRllb; each occurrence of Rg and Rh is, independently, hydrogen, alkyl, or alkynyl, or Rg and Rh together with the carbon atom to which they are attached form a carbonyl; t is 1, 2, or 3; each ence of R10 is, ndently, hydrogen or alkyl, n R10is optionally substituted with 1-3 independent substituents R ; each ence of Ro lla and Rlib is, independently, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, wherein each Rlla and Rllb are optionally substituted with 1-3 independent substituents R ; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, carboxyl, oxo, aryl, heteroaryl, heterocyclyl, NRaRb, -S(0)2RC, or -C02Rd; and each occurrence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(0)0Ci-6 alkyl, -6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
In certain embodiments, X is O or NR10. In n embodiments, X is O or NR10; and R10is hydrogen or alkyl. In certain embodiments, X is O. In certain ments, X is NR10. In certain embodiments, X is NR10; and R10is alkyl. In certain embodiments, X is NR10; and R10is Ci_4 alkyl. In certain embodiments, X is NR10; and R10 is methyl.
In n embodiments, Y is O or NR10. In certain embodiments, Y is O or NR10; and R10is hydrogen or alkyl. In certain embodiments, Y is O. In certain ments, Y is NR10. In n embodiments, Y is NR10; and R10is alkyl. In certain embodiments, Y is NR10; and R10is Ci_4 alkyl. In certain embodiments, Y is NR10; and R10 is methyl.
] In n embodiments, X is O or NR10; and Y is O or NR10. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is en or alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or C1-4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R5 is Ci_4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is methyl, ethyl, propyl, or butyl. In certain embodiments, X is O; Y is NR10; and R10 is C1-4 alkyl. In certain embodiments, X is O; Y is NR10; and R10is methyl, ethyl, propyl, or butyl.
In certain embodiments, X is O; Y is NR10; and R10is methyl.
In certain embodiments, Rg is hydrogen or alkyl. In certain embodiments, Rg is hydrogen or Ci_4 alkyl. In certain embodiments, Rg is hydrogen, halogen, or Ci_2 alkyl. In certain ments, Rg is hydrogen.
In certain embodiments, Rh is hydrogen or alkyl. In certain embodiments, Rh is hydrogen or Ci_4 alkyl. In certain embodiments, Rh is hydrogen or Ci_2 alkyl. In certain embodiments, Rh is hydrogen.
In certain embodiments, each occurrence of Rg and Rh is, independently, hydrogen or alkyl. In certain embodiments, each occurrence of Rg and Rh is, independently, hydrogen or C1-4 alkyl. In n embodiments, each occurrence of Rg and Rh is, independently, hydrogen, n, or Ci_2 alkyl. In certain embodiments, each occurrence of Rg and Rh is hydrogen. In certain embodiments, Rg and Rh together with the carbon atom to which they are attached form a carbonyl.
In n embodiments, t is 1, 2, or 3. In certain embodiments, t is 1 or 2. In certain embodiments, t is 1. In certain embodiments, t is 2. In certain embodiments, t is 3.
In certain embodiments, the compound of Formula I is a compound of Formula I-j: or a pharmaceutically acceptable salt thereof, wherein: In certain embodiments, X is O, NR10, or CRllaRllb; Y is O, NR10, or CRllaRllb; ed that at least one of X and Y is not CRllaRllb; each occurrence of R10 is, independently, en or alkyl, wherein R is optionally substituted with 1-3 independent tuents R ; each occurrence of Rlla and Rllb is, independently, alkyl, alkynyl, cycloalkyl, cycloalkylalkyl, wherein each Rlla and Rllb are optionally substituted with 1-3 independent substituents R8; each occurrence of R is, independently, alkyl, alkynyl, hydroxyl, alkoxy, yl, oxo, aryl, o heteroaryl, heterocyclyl, NRaRb, -S(0)2RC, or -COiR1'; and each occurrence of Ra, Rb, Rc, and Rd is, ndently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cyclylalkyl, aryl, aryl, heterocyclyl, C(0)OCi_6 alkyl, C(0)Ci_6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
In certain ments, X is O or NR10. In certain embodiments, X is O or NR10; and R10 is hydrogen or alkyl. In certain embodiments, X is O. In certain embodiments, X is NR10. In certain embodiments, X is NR10; and R10 is alkyl. In certain embodiments, X is NR10; and R10 is Ci_4 alkyl. In certain embodiments, X is NR10; and R10 is methyl.
In certain embodiments, Y is O or NR10. In n embodiments, Y is O or NR10; and R10is hydrogen or alkyl. In n embodiments, Y is O. In certain embodiments, Y is NR10. In certain embodiments, Y is NR10; and R10is alkyl. In certain embodiments, Y is NR10; and R10is Ci_4 alkyl. In certain embodiments, Y is NR10; and R10 is methyl.
In certain embodiments, X is O or NR10; and Y is O or NR10. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or alkyl. In certain ments, X is O or NR10; Y is O or NR10; and R10 is hydrogen or Ci_4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R5 is Ci_4 alkyl. In certain embodiments, X is O or NR10; Y is O or NR10; and R10 is methyl, ethyl, propyl, or butyl. In certain embodiments, X is O; Y is NR10; and R10 is C1-4 alkyl. In certain embodiments, X is O; Y is NR10; and R10is methyl, ethyl, propyl, or butyl.
In certain embodiments, X is O; Y is NR10; and R10is methyl.
] In certain embodiments, the compound of Formula I is a compound of the formula: or a pharmaceutically acceptable salt thereof.
Examples of the nd of Formula I e, but are not limited to (E)-N-(2-fluorophenyl)(3-methoxy(propyn-1 -yloxy)phenyl)acrylamide (1); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-lH-l,2,4-triazol yl)phenyl)acrylamide (2); (E)-N-(2-chlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (3); (E)-N-(2-bromophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (4); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(o-tolyl)acrylamide (5); (E)-N-(2-cyanophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (6); (E)-N-(3,4-dichlorophenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide (7); (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (16); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (17); (3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,2,4-oxadiazol yl)phenyl)-acrylamide (18); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-1,2,4- oxadiazol-3 -yl)phenyl)acrylamide (19); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (20); (E)-N-(2-(l,3,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (21); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-pyrazol yl)phenyl)-acrylamide (22); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)acryl-amide (23); (E)-N-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (24); (E)-N-(2-(lH-imidazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (25); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-imidazol yl)phenyl)acrylamide (26); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N- (methylsulfonyl)benzamide (27); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)phenyl)acryl-amide (28); (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-methyl-l,3,4-oxadiazol yl)phenyl)-acrylamide (29); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2H-tetrazol yl)benzamide (31); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methylpiperidin yl)benzamide (36); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(oxetan yl)benzamide (38); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (44); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- enzamide (47); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(l-methyl-lH-pyrazol- 3-yl)benzamide (48); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(piperidin yl)benzamide (49); (E)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid (51); (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76); ((E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamide (77); (3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)-benzoic acid (78); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79); 2-[[(E)(3-methoxypropynoxypyrrolidinyloxyphenyl)prop enoyl]amino]benzoic acid (80); (E)-N-(2-cyanophenyl)[3-methoxy(l-methylpyrrolidinyl)oxypropynoxyphenyl ]propenamide (81); (E)-N-(2-cyanophenyl)(3-methoxypropynoxypyrrolidinyloxy-phenyl)prop- 2-enamide (82); 2-[[(E)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (83); 2-[[(E)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (84); (2-cyanophenyl)[3-methoxy(2-morpholinoethoxy)propynoxyphenyl 2-enamide (85); 2-[[(E)[2-[3-(dimethylamino)propoxy]methoxypropynoxy-phenyl]prop enoyl]amino]benzoic acid (86); (E)-N-(2-cyanophenyl)[2-[3-(dimethylamino)propoxy]methoxypropynoxyphenyl ]propenamide (87); (E)-N-(2-cyanophenyl)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enamide (88); (E)-N-(2-cyanophenyl)[3-methoxy[(l-methylpiperidyl)oxy]propynoxyphenyl ]propenamide (89); 2-[[(E)[4-(cyclopropylmethoxy)[2-(dimethylamino)ethoxy]methoxyphenyl ]propenoyl]amino]benzoic acid (90); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (91); (E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (92); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (93); (E)-N-(2-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxy-phenyl]prop e (94); (E)(3-(3,4-dimethoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (95); (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96); (E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid (97); (E)(3-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (98); (E)(3-(3-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin nyl)acrylamido)benzoic acid (99); (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101); (E)(3-(3-methoxymorpholinophenyl)acrylamido)benzoic acid (103); (E)(3-(4-methoxy( 1-methyl-1,2,3,6-tetrahydropyridin yl)phenyl)acrylamido)benzoic acid (104); 2-[[(E)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (108); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (HO); (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (ill); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (112); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-lyl )phenyl)-acrylamide (114); (E)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116); chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamido)benzoic acid (117); (E)-N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (120); N-(4-cyanophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121); 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane- 1-carboxamide (122); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-fluorophenyl)acrylamide (123); (E)-A/-(4-cyanophcnyl)(3-cthyl(propyn-l -yloxy)phcnyl)acrylamidc (124); (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(4-fluorophenyl)acrylamide (125); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(2- fluorophenyl)acrylamide (127); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4- fluorophenyl)acrylamide (128); (E)-N-(4-cyanophenyl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamide (129); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (130); (E)-N-(4-cyanophenyl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylamide (131); (E)-N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidin )phenyl)acrylamide (132); luorophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (133); N-(4-cyanophenyl)(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxamide (135); N-(4-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (136); N-(4-cyanophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane- 1-carboxamide (137); N-(2-fluorophenyl)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (138); (E)-N-(4-cyanophenyl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (139); (E)(3-methoxy( 1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 - yl)phenyl) acrylamide (140); (E)-N-(2-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide (141); N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (143); 2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-lH-1,2,4- triazol-1 -yl)phenyl)cyclopropanecarboxamide (144); N-(2-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (145); (E)-N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147); hlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (148); N-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (149); (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151); (E)-N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (152); (E)-N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (153); N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (154); N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (155); WO 44620 N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (156); N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropanecarboxamide (157); 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(3- (methylsulfonyl)phenyl) ropanecarboxamide (158); (E)-N-(2-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylamide (159); (E)-N-(3-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylamide (160); and pharmaceutically acceptable salts thereof.
In another aspect, disclosed are the following nds: (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-phenylacrylamide (8); methyl (E)-l-(3-(3-methoxy(propyn-l-yloxy)phenyl)acryloyl)-l,2,3,4- tetrahydroquinolinecarboxylate (9) (E)-l-(3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop- 2-en-l-one (10); (E)-l-(3,4-dihydroquinoxalin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (11); (E)-l-(2,3-dihydro-4H-benzo[b][l,4]oxazinyl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (12); (E)-N-((trans)aminocyclohexyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (13); (E)-l-(4-hydroxy-3,4-dihydroquinolin-l(2H)-yl)(3-methoxy(propyn-lyloxy )phenyl)propen-1 -one (14); (3-hydroxy-lH-indazol-l-yl)(3-methoxy(propyn-l-yloxy)phenyl)prop en-l-one (15); (E)-N-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn lyloxy) phenyl) acrylamido) benzamide (30); (E)-N-(3-(dimethylamino)propyl)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido) benzamide (32); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2- methoxyethyl)benzamide (33); (3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(4-methylpiperazinl-yl )ethyl)benzamide (34); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-morpholino ethyl)benzamide (35); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methylpiperidin yl)methyl)benzamide (37); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((tetrahydrofuran yl)methyl)benzamide (39); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-((l-methyl-lH- imidazolyl)methyl)benzamide (40); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (41); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (42); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (43); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (45); (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N-(2-(pyridin yl)benzamide (46); (E)(3-(3-methoxy(piperidinylmethoxy)phenyl)acrylamido)benzoic acid (50); (E)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid (52); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (53); (E)(3-(3-methoxy(oxetanylmethoxy)phenyl)acrylamido)benzoic acid (54); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (55); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (56); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (57); (E)(3-(3-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (58); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (59); (E)(3-(3-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (60); (E)(3-(4-methoxy(2-methoxyethoxy)phenyl)acrylamido)benzoic acid (61); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (62); (E)(3-(4-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (63); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (64); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (65); (E)(3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (3-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (67); (E)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); (E)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic acid (70) (3-(4-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (71); (E)(3-(3-methoxy((propyn-l-yloxy)methyl)phenyl)acrylamido)benzoic acid (72); (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73); (E)(3-(4-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (74); (E)(3-(3-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid (75); (E)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100); 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102); (E)(3-(3-ethylmethoxyphenyl)acrylamido)benzoic acid (105); WO 44620 (E)(3-(3-(cyclopropylmethyl)methoxyphenyl)acrylamido)benzoic acid (106); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)prop- 2-en-l-one (113); (E)-1 enzo[b] [ 1,4]oxazin-4(3H)-yl)-3 -(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propen-1 -one (115); (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)propen-1 -one (118); (2H-benzo[b] [ azin-4(3H)-yl)(2-(3-methoxy(propyn-1 -yloxy) phenyl) cyclopropyl) methanone (119); (E)(3-ethyl(propyn-l-yloxy)phenyl)-l-(3-hydroxy-lH-indazol-l-yl)propen-l- one (126); (3-hydroxy- IH-indazol- l-yl)(2-(3-methoxy(propyn- l-yloxy)phenyl)cyclopropyl) methanone (134); (E)-l-(3-hydroxy-lH-indazol-l-yl)(3-methoxy( 1,2,3,6-tetrahydropyridin yl)phenyl)propen-l-one (142); (3-hydroxy-lH-indazol-l-yl)(2-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl) cyclopropyl)methanone (146); (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide (150); and ceutically able salts thereof.
For example, disclosed is a compound of the formula: or a pharmaceutically acceptable salt thereof.
In certain embodiments, the compound of Formula I inhibits TGF-P induced proline incorporation in cells with an IC50 of less than 100,000 pM, less than 50,000 pM, less than ,000 pM, less than 10,000 pM, less than 5,000 pM, less than 2,500 pM, less than 1,000 pM, less than 900 pM, less than 800 pM, less than 700 pM, less than 600 pM, less than 500 pM, less than 400 pM, less than 300 pM, less than 200 pM, less than 100 pM, less than 90 pM, less than 80 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 jaM, less than 10 jjM, less than 5 jjM, less than 4 jaM, less than 3 jaM, less than 2 jaM, or less than 1 jaM.
] In certain embodiments, any compound disclosed herein (e.g., 2-[[(£’)[4- propylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) inhibits TGF-P induced proline incorporation in cells with an IC50 of less than 100,000 pM, less than 50,000 pM, less than 20,000 pM, less than 10,000 pM, less than 5,000 pM, less than 2,500 pM, less than 1,000 pM, less than 900 pM, less than 800 pM, less than 700 pM, less than 600 pM, less than 500 pM, less than 400 pM, less than 300 pM, less than 200 pM, less than 100 pM, less than 90 pM, less than 80 pM, less than 70 pM, less than 60 pM, less than 50 pM, less than 40 pM, less than 30 pM, less than 20 pM, less than 10 pM, less than 5 pM, less than 4 pM, less than 3 pM, less than 2 pM, or less than 1 pM.
Pharmaceutical Compositions, Kits, and Administration The present disclosure provides pharmaceutical compositions comprising a nd {e.g., compound of Formula I, 2-[[(£’)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid) or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically ed tive, or prodmg thereof, and optionally a pharmaceutically acceptable excipient. In certain ments, the pharmaceutical composition described herein comprises a compound {e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt f, and a pharmaceutically acceptable excipient.
In certain embodiments, the compound {e.g., compound of a I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the effective amount is a therapeutically ive amount. In certain embodiments, the effective amount is a prophylactically effective amount. In n embodiments, the effective amount is an amount effective for treating a disease or condition associated with fibrosis in a subject in need thereof.
In certain embodiments, the effective amount is an amount effective for preventing disease or condition associated with fibrosis in a subject in need thereof. In certain ments, the effective amount is an amount effective for treating fibrotic skin disorders {e.g., keloids, hypertrophic scars, scleroderma) in a subject in need thereof. In certain embodiments, the ive amount is an amount effective for preventing fibrotic skin ers (e.g., keloids, hypertrophic scars, scleroderma) in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating kidney disease in a subject in need f.
In certain embodiments, the effective amount is an amount effective for preventing kidney e in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for treating an inflammatory disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing an inflammatory disease in a t in need thereof. In certain embodiments, the effective amount is an amount effective for treating a benign or malignant neoplastic disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for preventing a benign or ant neoplastic disease in a subject in need thereof. In certain embodiments, the effective amount is an amount effective for reducing the risk of developing a disease (e.g., fibrosis, fibrotic skin disorders, kidney disease, inflammatory disease, or benign or malignant neoplastic disease) in a subject in need thereof. In n embodiments, the ive amount is an amount effective for inhibiting the activity (e.g., aberrant activity, such as increased activity) of a protein in a subject or cell.
In certain embodiments, the subject is an . The animal may be of either sex and may be at any stage of development. In certain embodiments, the subject described herein is a human. In n embodiments, the subject is a non-human animal. In certain ments, the subject is a mammal. In certain embodiments, the subject is a non-human mammal. In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a companion animal, such as a dog or cat. In certain ments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a zoo animal. In another ment, the subject is a research animal, such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically engineered animal. In certain embodiments, the animal is a transgenic animal (e.g., transgenic mice and transgenic pigs). In n ments, the subject is a fish or reptile.
In certain embodiments, the effective amount is an amount effective for inhibiting the ty of the TGF-P signaling pathway by at least about 10%, at least about 20%, at least about %, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%. In certain embodiments, the effective amount is an amount effective for inhibiting the activity of the TGF-P signaling pathway by a range between a percentage described in this paragraph and another percentage described in this paragraph, inclusive.
The present disclosure provides pharmaceutical itions comprising a compound {e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid) for use in treating a disease or ion associated with is in a subject in need thereof. In certain embodiments, the composition is for use in treating fibrotic skin disorders {e.g., keloids, hypertrophic scars, scleroderma). In certain ments, the composition is for use in treating a lung disease {e.g., pulmonary is). In certain embodiments, the ition is for use in treating heart disease {e.g., ischaemic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the composition is for use in treating kidney disease. In certain embodiments, the composition is for use in treating cirrhosis of the liver. In certain embodiments, the composition is for use in treating kidney disease, wherein the kidney disease is progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, noproliferative glomerulonephritis, e proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic pathy.
A compound or composition, as described herein, can be administered in combination with one or more additional pharmaceutical agents {e.g., therapeutically and/or prophylactically active agents). The compounds or compositions can be administered in combination with additional pharmaceutical agents that improve their ty {e.g., activity {e.g., potency and/or cy) in treating a disease in a subject in need thereof, in preventing a disease in a subject in need thereof, and/or in reducing the risk to develop a e in a subject in need thereof), improve bioavailability, improve safety, reduce drug resistance, reduce and/or modify lism, inhibit excretion, and/or modify distribution in a subject or cell. It will also be iated that the therapy employed may achieve a desired effect for the same disorder, and/or it may achieve different effects. In certain embodiments, a pharmaceutical composition bed herein including a compound described herein and an additional ceutical agent exhibit a synergistic effect that is absent in a pharmaceutical composition including one of the compound and the additional pharmaceutical agent, but not both.
The compound or composition can be stered concurrently with, prior to, or subsequent to one or more additional pharmaceutical agents, which may be useful as, e.g., combination therapies. ceutical agents include therapeutically active agents.
Pharmaceutical agents also include prophylactically active . Pharmaceutical agents include small organic molecules such as drug compounds (e.g., compounds approved for human or veterinary use by the U.S. Food and Drug Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, tic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, ns, and cells. In certain embodiments, the additional pharmaceutical agent is a pharmaceutical agent useful for treating and/or preventing a disease (e.g., proliferative disease, hematological cancer, autoimmune disease, and/or inflammatory disease). Each additional pharmaceutical agent may be administered at a dose and/or on a time schedule determined for that pharmaceutical agent. The additional pharmaceutical agents may also be administered together with each other and/or with the compound or composition described herein in a single dose or administered separately in ent doses. The particular combination to employ in a regimen will take into account compatibility of the compound described herein with the additional pharmaceutical agent(s) and/or the desired therapeutic and/or prophylactic effect to be achieved. In general, it is expected that the additional pharmaceutical agent(s) in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some ments, the levels utilized in combination will be lower than those utilized individually.
The additional pharmaceutical agents e, but are not limited to, anti-proliferative agents, anti-cancer , ngiogenesis agents, anti-inflammatory agents, immunosuppressants, and anti-viral . In certain embodiments, the additional pharmaceutical agent is an anti-viral agent. In certain ments, the additional ceutical agent is an immunotherapy. In certain embodiments, the additional pharmaceutical agent is an anti-proliferative agent. In n embodiments, the additional pharmaceutical agent is an anti-cancer agent. In n embodiments, the anti-cancer agents include, but are not limited to, epigenetic or transcriptional modulators (e.g., DNA methyltransferase inhibitors, histone deacetylase inhibitors (HDAC inhibitors), lysine methyltransferase inhibitors), antimitotic drugs (e.g., taxanes and vinca alkaloids), cell signaling pathway inhibitors (e.g., tyrosine protein kinase tors), modulators of protein stability (e.g., proteasome inhibitors), Hsp90 inhibitors, glucocorticoids, all-trans retinoic acids, anti-estrogens (e.g., tamoxifen, raloxifene, and megestrol), LHRH ts (e.g., goscrclin and leuprolide), anti­ androgens (e.g. flutamide and tamide), photodynamic therapies (e.g., vertoporfin (BPDMA ), phthalocyanine, photosensitizer Pc4, and demethoxy-hypocrellin A (2BADMHA)), en ds (e.g., cyclophosphamide, ifosfamide, trofosfamide, chlorambucil, estramustine, and melphalan), nitrosoureas (e.g., carmustine (BCNU) and lomustine (CCNU)), alkylsulphonates (e.g., busulfan and treosulfan), triazenes (e.g. dacarbazine, temozolomide), platinum ning compounds (e.g. cisplatin, carboplatin, oxaliplatin), vinca alkaloids (e.g. vincristine, vinblastine, vindesine, and vinorelbine), taxoids (e.g. paclitaxel or a paclitaxel equivalent such as nanoparticle albumin-bound paclitaxel (ABRAXANE), docosahexaenoic acid paclitaxel (DHA-paclitaxel, Taxoprexin), polyglutamate bound-paclitaxel (PG-paclitaxel, paclitaxel poliglumex, 3, XYOTAX), the tumor-activated prodmg (TAP) 5 pep-2 bound to three molecules of paclitaxel), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognizing peptide EC-1), and glucose-conjugated paclitaxel, e.g., 2'-paclitaxel methyl 2- glucopyranosyl succinate; docetaxel, taxol), epipodophyllins (e.g. etoposide, etoposide phosphate, teniposide, topotecan, 9-aminocamptothecin, camptoirinotecan, irinotecan, crisnatol, mytomycin C), etabolites, DHFR inhibitors (e.g. methotrexate, dichloromethotrexate, trimetrexate, edatrexate), IMP dehydrogenase inhibitors (e.g. enolic acid, tiazofurin, ribavirin, and EICAR), ribonuclotide reductase inhibitors (e.g. hydroxyurea and deferoxamine), uracil analogs (e.g. 5-fluorouracil (5-FU), floxuridine, doxifluridine, exed, tegafur-uracil, capecitabine), cytosine analogs (e.g. bine (ara C), cytosine arabinoside, and fludarabine), purine analogs (e.g. mercaptopurine and Thioguanine), Vitamin D3 analogs (e.g. EB 1089, CB 1093, and KH 1060), isoprenylation inhibitors (e.g. lovastatin), nergic neurotoxins (e.g. l-methylphenylpyridinium ion), cell cycle inhibitors (e.g. staurosporine), actinomycin (e.g. mycin D, dactinomycin), bleomycin (e.g. bleomycin A2, bleomycin B2, peplomycin), cycline (e.g. daunorubicin, doxorubicin, pegylated liposomal doxorubicin, idarubicin, epimbicin, pirarubicin, zorubicin, mitoxantrone), MDR inhibitors (e.g. verapamil), Ca2+ ATPase WO 44620 tors (e.g. thapsigargin), thalidomide, lenalidomide, pomalidomide, tyrosine kinase inhibitors (e.g., axitinib (AG013736), bosutinib (SKI-606), nib (RECENTINTM, AZD2171), dasatinib (SPRYCEL®, BMS-354825), erlotinib (TARCEVA®), gefitinib (IRESSA®), imatinib (Gleevec®, CGP57148B, STI-571), lapatinib (TYKERB®, TYVERB®), lestaurtinib (CEP-701), neratinib (HKI-272), nib (TASIGNA®), semaxanib (semaxinib, SU5416), sunitinib (SUTENT®, SU11248), toceranib (PALLADIA®), vandetanib MA®, ZD6474), vatalanib (PTK787, PTK/ZK), trastuzumab (HERCEPTIN®), bevacizumab (AVASTIN®), rituximab (RETUXAN®), cetuximab (ERBITUX®), panitumumab (VECTIBIX®), ranibizumab (Lucentis®), nilotinib (TASIGNA®), sorafenib (NEXAVAR®), everolimus (AFINITOR®), alemtuzumab (CAMPATH®), umab ozogamicin (MYLOTARG®), temsirolimus (TORISEL®), ENMD-2076, PCI-32765, AC220, dovitinib lactate (TKI258, CHIR-258), BIBW 2992 (TOVOKTM), SGX523, PF-04217903, PF-02341066, PE-299804, BMS-777607, ABT-869, MP470, BIBE 1120 (VARGATEF®), AP24534, JNJ- 26483327, 5, DCC-2036, BMS-690154, CEP-11981, tivozanib (AV-951), OSI-930, MM-121, XL-184, XL-647, and/or XL228), proteasome inhibitors (e.g., bortezomib (VELCADE)), mTOR inhibitors (e.g., cin, temsirolimus (CCI-779), everolimus (RAD- 001), ridaforolimus, AP23573 (Ariad), AZD8055 (AstraZeneca), BEZ235 (Novartis), BGT226 (Norvartis), XL765 (Sanofi Aventis), PF-4691502 (Pfizer), GDC0980 (Genetech), SF1126 (Semafoe) and OSI-027 (OSI)), oblimersen, gemcitabine, carminomycin, leucovorin, pemetrexed, cyclophosphamide, dacarbazine, procarbizine, prednisolone, dexamethasone, hecin, plicamycin, asparaginase, aminopterin, methopterin, porfiromycin, melphalan, leurosidine, leurosine, chlorambucil, trabectedin, procarbazine, discodermolide, carminomycin, aminopterin, and hexamethyl melamine.
In certain ments, the compounds bed herein or pharmaceutical itions can be stered in combination with an anti-cancer therapy including, but not limited to, surgery, radiation therapy, and transplantation (e.g., stem cell transplantation, bone marrow transplantation).
] In certain embodiments, the compound or pharmaceutical composition is a solid. In certain embodiments, the compound or pharmaceutical ition is a powder. In certain ments, the compound or pharmaceutical ition can be dissolved in a liquid to make a solution. In certain embodiments, the compound or pharmaceutical ition is dissolved in water to make an aqueous solution. In certain embodiments, the pharmaceutical composition is a liquid for parental injection. In certain ments, the pharmaceutical composition is a liquid for oral administration (e.g., ingestion). In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for intravenous ion. In certain embodiments, the pharmaceutical composition is a liquid (e.g., aqueous solution) for subcutaneous injection.
After formulation with an appropriate pharmaceutically acceptable excipient in a desired dosage, the ceutical compositions of this invention can be administered to humans and other animals orally, parenterally, intracisternally, intraperitoneally, topically, bucally, or the like, depending on the disease or condition being treated.
In certain ments, a pharmaceutical composition comprising a compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid) is stered, orally or parenterally, at dosage levels of each pharmaceutical composition sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg in one or more dose strations for one or several days (depending on the mode of stration). In certain ments, the effective amount per dose varies from about 0.001 mg/kg to about 200 mg/kg, about 0.001 mg/kg to about 100 mg/kg, about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about mg/kg, from about 0.1 mg/kg to about 10 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. In certain embodiments, the compounds described herein may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 200 mg/kg, from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more ably from about 1 mg/kg to about 25 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic and/or prophylactic effect. The desired dosage may be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the d dosage may be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). In certain embodiments, the composition described herein is administered at a dose that is below the dose at which the agent causes non-specific effects.
In certain embodiments, the ceutical composition is administered at a dose of about 0.001 mg to about 1000 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 200 mg per unit dose. In certain embodiments, the ceutical composition is administered at a dose of about 0.01 mg to about 100 mg per unit dose. In certain embodiments, pharmaceutical ition is administered at a dose of about 0.01 mg to about 50 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.01 mg to about 10 mg per unit dose. In certain embodiments, the pharmaceutical composition is administered at a dose of about 0.1 mg to about 10 mg per unit dose.
Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the composition comprising a compound {e.g., compound of Formula I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) into ation with a carrier and/or one or more other ory ients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.
Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" is a te amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage, such as, for example, one-half or one-third of such a dosage.
Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any onal ients in a ceutical ition of the invention will vary, depending upon the identity, size, and/or condition of the t treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ient.
Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, egrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, ing, and perfuming agents may also be t in the composition.
Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium en phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, ol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures f.
Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch ate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose, and wood products, natural sponge, cation-exchange resins, calcium ate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch m starch ate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium um silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and es thereof.
Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite (aluminum silicate) and Veegum sium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g. l alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl r), eenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, ed cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60), an tristearate (Span 65), glyceryl monooleate, sorbitan eate (Span 80)), polyoxyethylene esters (e.g. polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor™), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, anolamine oleate, sodium oleate, ium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F-68, Poloxamer-188, onium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof. ary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, n, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, rystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.
Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives. In n embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.
Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated yanisole, ted hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.
Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, ium edetate, calcium disodium e, dipotassium edetate, and the like), citric acid and salts and es thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates f, phosphoric acid and salts and es thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, ide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, , ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, mercuric nitrate, propylene glycol, and thimerosal. ary antifungal preservatives include butyl n, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.
Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, ybenzoate, and phenylethyl alcohol.
Exemplary acidic preservatives include vitamin A, vitamin C, n E, betacarotene , citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.
Other preservatives include erol, tocopherol acetate, xime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl e (SLS), sodium lauryl ether e (SEES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl.
Exemplary buffering agents include citrate buffer ons, acetate buffer solutions, ate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium tate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium nate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, ic calcium phosphate, calcium hydroxide ate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, c acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.
Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, yl behanate, hydrogenated vegetable oils, hylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and es thereof.
Exemplary l oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, , cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, com, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazelnut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, foam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, ne, soybean, wer, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, symps, and elixirs. In addition to the active agents, the liquid dosage forms may contain inert diluents ly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl l, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene , dimethylformamide, oils (in ular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures f. Besides inert diluents, oral compositions can also include adjuvants such as wetting agents, fying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, agents of the invention are mixed with solubilizing agents such CREMOPHOR EL® thoxylated castor oil), alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.
Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions, may be formulated ing to the known art using suitable sing or wetting agents and ding agents. Sterile injectable preparation may also be a sterile injectable solution, sion or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a on in 1,3-butanediol. Among the able vehicles and solvents that may be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride on. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.
Injectable formulations can be sterilized, for example, by tion through a bacterial- retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in e water or other sterile injectable medium prior to Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active agent is mixed with at least one inert, ceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, e, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and ol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be ed as fillers in soft and hardfilled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other gs well known in the pharmaceutical formulating art. They may optionally n opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the inal tract, optionally, in a delayed manner.
Examples of embedding compositions which can be used include polymeric nces and waxes. Solid compositions of a similar type may also be ed as fillers in soft and hardfilled n capsules using such excipients as lactose or milk sugar as well as high molecular weight hylene glycols and the like.
The active agents can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the ceutical formulating art. In such solid dosage forms the active agent may be admixed with at least one inert diluent such as sucrose, lactose or . Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other ing aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may also se buffering agents. They may optionally n opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
Formulations suitable for topical stration e liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments, or pastes; or solutions or suspensions such as drops. Formulations for topical administration to the skin surface can be prepared by dispersing the drug with a dermatologically acceptable carrier such as a , cream, ointment, or soap. Useful carriers are e of g a film or layer over the skin to localize application and inhibit removal. For l administration to internal tissue surfaces, the agent can be dispersed in a liquid tissue adhesive or other substance known to enhance adsorption to a tissue surface. For example, hydroxypropylcellulose or fibrinogen/thrombin solutions can be used to advantage.
Alternatively, tissue-coating solutions, such as pectin-containing formulations can be used.
Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of this invention. Additionally, the present disclosure contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of an agent to the body. Such dosage forms can be made by dissolving or dispensing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the agent across the skin.
The rate can be lled by either providing a rate controlling membrane or by dispersing the agent in a polymer matrix or gel.
Additionally, the carrier for a topical ation can be in the form of a hydroalcoholic system (e.g., quids and gels), an anhydrous oil or silicone based system, or an emulsion system, including, but not limited to, oil-in-water, water-in-oil, in-oil-in-water, and oil-in-water-in-silicone emulsions. The ons can cover a broad range of consistencies including thin lotions (which can also be suitable for spray or aerosol delivery), creamy lotions, light , heavy creams, and the like. The emulsions can also include mulsion systems. Other suitable topical carriers include anhydrous solids and semisolids (such as gels and sticks); and aqueous based mousse systems.
Also encompassed by the disclosure are kits {e.g., ceutical . The kits provided may comprise a pharmaceutical composition or compound bed herein and a container {e.g., a vial, ampule, bottle, syringe, and/or dispenser e, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a pharmaceutical excipient for dilution or suspension of a ceutical ition or compound described herein. In some embodiments, the ceutical composition or compound described herein provided in the first container and the second container are combined to form one unit dosage form.
Thus, in one aspect, provided are kits including a first container comprising a compound or pharmaceutical composition described herein. In certain embodiments, the kits are useful for treating a disease {e.g., proliferative disease, hematological cancer, autoimmune disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for preventing a disease {e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a t in need thereof. In n embodiments, the kits are useful for reducing the risk of developing a disease {e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits are useful for inhibiting the activity {e.g., aberrant activity, such as increased activity) of the TGF-P ing pathway in a subject or cell.
In certain embodiments, a kit described herein further includes instructions for using the kit. A kit described herein may also include information as required by a regulatory agency such as the U.S. Food and Drug Administration (FDA). In n embodiments, the information included in the kits is prescribing ation. In certain embodiments, the kits and instructions provide for treating a disease {e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain WO 44620 ments, the kits and instructions provide for preventing a disease (e.g., a disease or condition associated with fibrosis, a benign or ant neoplastic disease, inflammatory disease) in a subject in need thereof. In certain embodiments, the kits and instructions provide for ng the risk of ping a disease (e.g., a disease or condition associated with fibrosis, a benign or malignant neoplastic disease, inflammatory e) in a subject in need thereof. In certain embodiments, the kits and instructions provide for inhibiting the activity (e.g., aberrant activity, such as increased activity) of the TGF-P signaling pathway in a subject or cell. A kit described herein may include one or more additional pharmaceutical agents described herein as a te composition.
Methods of Treatment Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process, and the deposition of connective tissue can obliterate the architecture and on of the underlying organ or tissue. Fibrosis is the pathological state of excess deposition of fibrous tissue, as well as the process of connective tissue deposition in healing. Defined by the pathological accumulation of extracellular matrix (ECM) ns, fibrosis results in scarring and thickening of the affected tissue. Thus, it is an exaggerated wound healing response which interferes with normal organ function.
The most well characterized pro-fibrotic mediator is TGF-P, which is released by hages as well as any damaged tissue between surfaces called interstitium. Other soluble mediators of fibrosis include connective tissue growth factor , platelet-derived growth factor (PDGF), and Interleukin 4 (IL-4). These te signal transduction pathways such as the AKT/mTOR and SMAD pathways that tely lead to the proliferation and activation of fibroblasts, which deposit extracellular matrix into the surrounding tive tissue. Therefore, use of a compound that inhibits mediators of fibrosis (e.g., TGF-P) provides a method of treating diseases that rely on fibrotic activity.
The present disclosure provides methods for treating a disease or condition associated with fibrosis. In certain ments, the application provides a method of treating fibrotic skin disorders (e.g., s, hypertrophic scars, scleroderma). In certain embodiments, the application provides a method of treating lung disease (e.g., pulmonary fibrosis). In certain ments, the application provides a method of treating heart disease (e.g., ischaemic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the application provides a method of treating cirrhosis of the liver. In certain embodiments, the application provides a method of treating kidney disease.
In n embodiments, the application provides a method of treating progressive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic pathy. In certain ments, the application provides a method of treating focal segmental glomerulosclerosis. In certain embodiments, the application provides a method of treating benign or malignant neoplastic disease. In certain embodiments, the application provides a method of treating inflammation. In certain ments, the application provides a method of inhibiting the TGF-P signaling pathway.
In n embodiments, the methods comprise administering to a t in need thereof (e.g., a subject ing from a disease associated with fibrosis) a compound that interacts with TGF-P, for example, a compound that is an inhibitor of TGF-P or the TGF-P signaling pathway. In certain embodiments, the methods comprise administering a compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]prop enoyl]amino]benzoic acid), or a pharmaceutically able salt, co-crystal, tautomer, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof. In some ments, the method comprises administering a pharmaceutical composition comprising a compound (e.g., nd of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, stal, tautomer, stereoisomer, solvate, hydrate, rph, isotopically enriched derivative, or prodrug, or composition thereof, to a subject in need thereof.
The present disclosure also provides a compound (e.g., compound of Formula I, 2- [[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, co-crystal, tautomer, stereoisomer, solvate, e, polymorph, isotopically ed derivative, or prodrug, or ition thereof, for use in the treatment of a disease or condition ated with fibrosis, benign or malignant neoplastic disease, or inflammation. In n ments, the disease or condition associated with fibrosis is fibrotic skin disorders (e.g., keloids, hypertrophic scars, scleroderma). In certain embodiments, the disease or condition associated with fibrosis is lung disease (e.g., pulmonary fibrosis). In certain embodiments, the disease or condition ated with fibrosis is heart disease (e.g., ischaemic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the disease or condition associated with fibrosis is cirrhosis of the liver. In certain embodiments, the disease or ion associated with fibrosis is kidney disease. In certain embodiments, the kidney e is kidney disease is progressive kidney disease, ulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, noproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy.
The present disclosure also provides uses of a compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a ceutically acceptable salt, co-crystal, er, isomer, solvate, hydrate, polymorph, isotopically enriched derivative, or g, or composition thereof, in the manufacture of a medicament for the treatment of a disease or condition associated with is, benign or malignant neoplastic disease, or inflammation. In certain embodiments, the disease or condition associated with is is fibrotic skin disorders (e.g., keloids, hypertrophic scars, scleroderma).
In certain embodiments, the disease or condition associated with fibrosis is lung disease (e.g., pulmonary fibrosis). In certain embodiments, the e or condition associated with fibrosis is heart disease (e.g., ischaemic heart disease, valvular heart disease, hypertensive heart disease, diabetic cardiomyopathy, hypertension). In certain embodiments, the disease or condition associated with fibrosis is cirrhosis of the liver. In certain ments, the disease or condition associated with is is kidney disease. In certain embodiments, the kidney disease is kidney disease is ssive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse erative glomerulonephritis, membranous focal tal glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy.
In certain embodiments, the s of the invention comprise administering to the subject an effective amount of a nd (e.g., compound of Formula I, )[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or a pharmaceutically acceptable salt, stal, er, stereoisomer, solvate, hydrate, polymorph, isotopically enriched derivative, or prodrug, or composition thereof. In some embodiments, the effective amount is a therapeutically effective amount. In some embodiments, the effective amount is a lactically effective amount.
In certain embodiments, the subject being treated is an animal. The animal may be of either sex and may be at any stage of development. In certain ments, the subject is a mammal. In certain embodiments, the subject being treated is a human.In certain embodiments, the subject is a domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or goat. In certain embodiments, the subject is a ion animal, such as a dog or cat. In certain embodiments, the subject is a livestock animal, such as a cow, pig, horse, sheep, or goat. In n embodiments, the subject is a zoo animal. In r embodiment, the subject is a research animal such as a rodent (e.g., mouse, rat), dog, pig, or non-human primate. In certain embodiments, the animal is a genetically ered animal. In certain embodiments, the animal is a transgenic animal.
Certain methods described herein may comprise administering one or more additional pharmaceutical agent(s) in combination with the compounds described herein. The additional ceutical agent(s) may be administered at the same time as the compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid), or at different times than the compound (e.g., nd of a I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid). For example, the compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid) and any additional pharmaceutical agent(s) may be on the same dosing schedule or different dosing schedules. All or some doses of the compound (e.g., compound of Formula I, 2-[[(E)[4-(cyclopropylmethyl) methoxyphenyl]propenoyl]amino]benzoic acid) may be administered before all or some doses of an additional pharmaceutical agent, after all or some does an additional pharmaceutical agent, within a dosing schedule of an additional pharmaceutical agent, or a combination thereof. The timing of administration of the compound (e.g., compound of Formula I, 2-[[(E)[4- (cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid) and additional pharmaceutical agents may be different for different additional pharmaceutical agents.
Examples In order that the invention described herein may be more fully tood, the following examples are set forth. The examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and s provided herein and are not to be construed in any way as limiting their scope.
Mass spectra were recorded on a Micromass ZQ™, single quadrapole mass ometer. ^ r magnetic resonance (NMR) spectroscopy was carried out using a Bmker instrument operating at 400 MHz using the stated solvent at around room temperature, unless otherwise stated. Characteristic chemical shifts (8) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad.
Preparative HPLC purification was accomplished using the following platforms: Reverse phase preparative-HPLC using a Gilson preparative HPLC system (322 pump; 156 UV/ VIS detector; GX281 liquid handler). The GX281 liquid handler acted as both auto-sampler and fraction collector. Preparative purification was performed using Phenomenex Gemini C18 at 150 x 25 mm x 10 pm or YMC -Actus Triart C18 150 x 30 mm x 5 pm columns. Appropriate focused gradients were selected based on itrile and methanol t systems under acidic or basic ions. The standard gradient used 20% gradient difference over 10 min. After each run a 2.0 min 100% itrile wash was performed followed by a 1.5 min re-equilibration at the initial conditions. A flow rate of 25 mL/min was used throughout. The modifiers used for /basic conditions were trifluoroacetic acid aqueous (0.1% v/v), a (0.05% v/v; pH = ) and hydrochloric acid aqueous (0.1% v/v) respectively. The purification was controlled by Trilution LC software and triggered by a threshold collection value at 220 nm or 254 nm.
Collected ons were analyzed by LCMS (Agilent LCMS with 1100/1200 LC systems and 6110/6140 Mass System). The fractions that contained desired product were trated by vacuum centrifugation and the resultant e passed through a freeze-drying cycle.
Alternatively, preparative HPLC purification was performed by reverse phase HPLC using a Waters Fractionlynx preparative HPLC system (2525 pump, 2996/2998 UV/VIS TM detector, 2767 liquid handler) or an lent HPLC system such as a Gilson Trilution® UV directed system. The Waters® 2767 liquid handler acted as both auto-sampler and fraction collector. The columns used for the preparative purification of the compounds were a Waters Sunfire® OBD Phenomenex Luna® Phenyl Hexyl or Waters e® Phenyl at 10 pm 19 x 150 mm or Waters CSH Phenyl Hexyl, 19 x 150 mm, 5 pm column. Appropriate focused gradients TM were selected based on acetonitrile and methanol solvent systems under either acidic or basic conditions. The ers used under acidic/basic conditions were formic acid or trifluoroacetic acid (0.1% V/V) and ammonium onate (10 mM) respectively. The purification was lled by Waters Fractionlynx software through monitoring at 210-400 nm, and triggered aTM threshold collection value at 260 nm and, when using the onlynx , the presence of target TM molecular ion as observed under APi conditions. Collected fractions were analyzed by LCMS (Waters Acquity® systems with Waters® SQD).
Analytical methods Analytical Method 1: Using an Agilent 1200\G1956A LC-MS spectrometer and an Agilent 1200\G1956A. Method details are: 1) mobile phase: A: 0.025% NH3*H20 in water ( v/v) ; B: Acetonitrile ; 2) Gradient: B% from 10% to 80% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD 220nm & 254nm.
Analytical Method 2: Analytical UPLC-MS was performed on a Waters Acquity I- Class UPLC with Waters Diode Array Detector (210-400 nm) coupled to a Waters SQD2 single quadrapole UPLC mass spectrometer using an HSS C18 column (1.8um 100 x 2.1mm plus . Method details are: 1) mobile phase: A: 0.1% formic acid (v/v) in water; B: 0.1% formic acid (v/v) in acetonitrile; 2) Gradient 0-1.2 min 95% A 5% B, 1.2 -3.5 min linear gradient to 0% A 100% B, 3.5-4.9 min 0% A 100% B, 4.9 - 5.0 min gradient to 95% A 5% B, 5.0 min - 6.0 min 95% A to 5% B. 3) Flow rate 0.5 mL/min.
Analytical Method 3: ical UPLC-MS was performed on a Waters Acquity I- Class UPLC with Waters Diode Array Detector (210-400 nm) coupled to a Waters SQD2 single quadrapole UPLC mass ometer using a BEH Shield RP18 column (1.7um 100 x 2.1mm. plus guard dge). Method details are: 1) mobile phase: A: lOmM ammonium bicarbonate in WO 44620 water; B: acetonitrile; 2) Gradient 0-1.2 min 95% A 5% B, 1.2 -3.5 min linear gradient to 0% A 100% B, 3.5-4.9 min 0% A 100% B, 4.9 - 5.0 min nt to 95% A 5% B, 5.0 min - 6.0 min 95% A to 5% B. 3) Flow rate 0.5 .
Analytical Method 4: Using an Agilent 1200 LC & Agilent 6110 MSD system and an Agilent Eclipse Plus C18 4.6*100mm 3.5pm. Method details are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v)); 2) Gradient: B% from 0% to 60% within 6 mins. 3) Flow rate: 1.0 mL/min. 4) Column Temp: 50°C; 5) or: DAD 210nm, 215nm, 220nm & 254nm.
Analytical Method 5: Using a SHIMADZU LCMS-2020 system and a Chromolith® Flash RP-18E 25-2 MM. Method details are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v)); 2) Gradient: B% from 0% to 60% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: PDA 220nm & 254nm.
Analytical Method 6: Using an Agilent 1200\G1956A system and a Xbridge C18 2.1*50 mm, Sum. Method s are: 1) mobile phase: A: 0.025% NFUfUO in water (v/v) ; B: itrile; 2) Gradient: B% from 0% to 60% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) or: DAD 220nm & 254nm.
Analytical Method 7: Using a SHIMADZU LC-20AB system and an Innovation C18 UPLC Column 2.1X30mm,2.6um. Method details are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 80% within 5.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: PDA(220nm, 254nm & 215nm).
Analytical Method 8: Using an Agilent 1200\G1956A system and a Xbridge C18 2.1*50mm, Sum. Method details are: 1) mobile phase: A: 0.025% NHyHiO in water (v/v; B: Acetonitrile; 2) Gradient: B% from 0% to 80% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD (220 & 254nm).
Analytical Method 9: Using a SHIMADZU 020 system and a Chromolith® Flash RP-18E 25-2 MM. Method details are: 1) mobile phase: A: 0.0375% TEA in water (v/v); B: 0.01875% TEA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 95% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: PDA (220nm & 254nm).
Analytical Method 10: Using an Agilent 1200\G1956A system and a Chromolith® Flash RP-18E 25-2 MM. Method details are: 1) mobile phase: A: % TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 95% within 3.5 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: DAD (220nm & 254nm).
Analytical Method 11: Using an Agilent 1200 LC & Agilent 6110 MSD system and an Agilent ZORBAX 5pm SB-Aq, 2.1*50mm. Method details are: 1) mobile phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); 2) Gradient: B% from 0% to 90% within 3.4 mins. 3) Flow rate: 0.8 . 4) Column Temp: 50°C; 5) or: DAD , 215nm, 220nm & 254nm).
Analytical Method 12: Using an Agilent 1200 LC & Agilent 6110 MSD system and an Agilent ZORBAX 5pm SB-Aq, 2.1*50mm. Method details are: 1) mobile phase: A: 0.0375% TFA in water (v/v); B: 0.01875% TFA in Acetonitrile (v/v); 2) Gradient: B% from 10% to 100% within 3.4 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 50°C; 5) Detector: DAD (210nm, 215nm, 220nm & .
Analytical Method 13: Using an Agilent 1200 LC & Agilent 6110 MSD system and a Agilent ZORBAX 5pm SB-Aq, 2.1*50mm. Method details are: 1) mobile phase: A: A: 0.05% NFF-fUO in water (v/v); B: Acetonitrile (v/v); 2) Gradient: B% from 5% to 90% within 3.4 mins. 3) Flow rate: 0.8 mL/min. 4) Column Temp: 40°C; 5) Detector: DAD (210nm, 215nm, 220nm & 254nm).
General Methods (R6)m (R6)m Z-R3 HO Z-R3 O R2-Y. (COR7)„ R2-Y 70 N R'-X R1-X 1-A 1-C Many of the compounds described below can be prepared ing to the scheme above. An de (1-A where X-R , Y-R , and Z-R can represent appropriate substituents) is reacted with an 3-oxo(phenylamino)propanoic acid (1-B in which R6 and R7can be appropriate substituents) to afford the desired /V-phenylcinnamamide analogues (1-C). This condensation is typically performed at an elevated temperature, for example 110°C, in a suitable solvent such as toluene or pyridine over a reaction time consistent with the reactivity of the substrates, for e 16 hours. The on is typically catalyzed by a suitable base such as piperidine. The starting materials 1-A and 1-B can be commercially available or prepared according to methods known to those skilled in the art. Suitable tuted N- phenylcinnamamide products (1-C) can also be further tized.
(R6)m (R6)m Z-R3 Z-R3 0 Z-R3 0 2B (COR7)n r2-y- r2-y. r2-y. ■0 "OR20 H (COR7)n R1-X R'-X r'-x 1-A 2-A 1-C Alternatively, de 1-A can be converted to the ic acid (2-A, where R 20 can be either H or a substituent such as methyl or ethyl) by reaction with malonic acid or a malonic acid monoester (scheme above). Such reactions are typically med in a solvent such as pyridine in the presence of a suitable base, for example piperidine, and are conducted at an elevated temperature for example 100 to 120 °C. Alternatively, the transformation can be accomplished using a Wittig or rth-Emmons reaction in which the aldehyde is reacted with a phosphonate, such as triethylphosphonoacetate, in the presence of a base, such as sodium hydride, and in an aprotic solvent such as THE. These reactions are commonly med at ambient temperature. Cinnamyl esters formed in this way can be converted to the acid using a hydroxide base. Alternatively the cinnamic acids or cinnamyl esters can be cially available or prepared from commercially available cinnamic acids or esters.
The cinnamic acid 2-A is converted to the /V-phenylcinnamamide 1-C using a coupling agent such as HATU in the presence of a suitable base, for example diisopropylethylamine and the aniline 2-B. These reactions are performed in an inert solvent such as dichloromethane or iV.iV-di methyl formamidc and can be performed at room temperature or elevated temperature depending on the reactivity of the substrates. Alternatively, the acid (2-B) can first be transformed into an acid chloride using, for example, oxalyl chloride. The acid chloride is then reacted with an aniline (2-C) in the presence of a suitable base such as trimethylamine or ne and in an inert solvent such as dichloromethane or tetrahydrofuran.
The starting materials 2-A or 2-B can be cially available or prepared according to methods known to those skilled in the art. The /V-phenylcinnamamide products can also be further modified.
WO 44620 Compound Synthesis (/?)-Af-(2-fluorophenyl)(3-methoxy(propyn- l-yloxy)phenyl)acrylamide (1) o o .0. .0.
'OH N H2N H To a suspension of (£’)(3-methoxypropynoxy-phenyl)propenoic acid (0.5 g, 2.15 mmol, 1.0 ) in dichloromethane (5 mL) was added oxalyl chloride (376 pL, 4.30 mmol, 2.0 equiv.) and the mixture was d at 25 °C for 30 minutes. The reaction mixture was concentrated under reduced pressure to give -(3-methoxy(propyn-lyloxy )phenyl)acryloyl chloride as a yellow solid, which was used directly t further purification (0.6 g).
To a solution of 2-fluoroaniline (46 pL, 0.479 mmol, 1.2 equiv.) in dichloromethane (5 mL) was added (£’)(3-methoxypropynoxy-phenyl)propenoyl chloride (0.1 g, 0.399 mmol, 1.0 equiv.) and triethylamine (166 pL, 1.20 mmol, 3.0 equiv.) and the mixture was stirred at 25 °C for 12 hours. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to give the desired product as a yellow solid (0.030 g, 23 %); H NMR , 400 MHz) 5 8.07 - 8.05 (m, 1H), 7.63 (d, /= 15.6 Hz, 1H), 7.26 -7.24 (m, 1H), 7.20 - 7.16 (m, 4H), 7.09 (d, /= 8.4 Hz, 1H), 6.84 (d, 7= 15.6 Hz, 1H), 4.81 (d, /= 2.4 Hz, 2H), 3.91 (s, 3H), 2.98 (t, / = 2.4 Hz, 1H); MS (ESI+) m/z 326.2 (M+H)+; 99.5% purity, RT 2.31 min (Method 10).
Ex Structure Data Method o 1H NMR (DMSO-d6, 400 MHz) 5 ed according 2 .0. % N 12.99 (hr. s„ 1H), 8.66 (d, J = 7.2 H to the method for 1 hr N Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), HN^ starting from 2-(5- 7.61 (d, J = 15.6 Hz, 1H), 7.35 (s, mcthyl-1 H-\ ,2,4- (E)(3-methoxy(propyn- 1H), 7.26 - 7.23 (m, 2H), 7.09 - 7.07 triazolyl)aniline l-yloxy)phenyl)-N-(2-(5-methyl- (m, 2H), 6.69 (d, J = 15.6 Hz, 1H), 1H-1,2,4-triazol 4.85 (d, J = 2.0 Hz, 2H), 3.86 (s, yl)phenyl)acrylamide 3H), 3.59 (t, J = 2.0 Hz, 1H), 2.41 (s, 3H); MS (ESI+) m/z 389.3 (M+H)+; 98.6% purity, RT 1.99 min (Method 8) 3 1H NMR (CD3OD, 400 MHz) 5 7.96 0 1^ Prepared according N (d, J = 8.0 Hz, 1H), 7.64 (d, / = 15.6 H to the method for 1 Cl Hz, 1H), 7.47 (d, J = 6.8 Hz, 1H), starting from 2- (£)-/V-(2-chl()i'ophcnyl)(3- 7.30 - 7.29 (m, 1H), 7.28 - 7.27 (m, chi oroani line methoxy(propyn-l - 1H), 7.19 - 7.18 (m, 2H), 7.12 - 7.10 yloxy)phenyl)acrylamide (m, 1H), 7.00 (d, J = 15.6 Hz, 1H), 4.81 (d, J = 2.4 Hz, 2H), 3.90 (s, 3H), 2.98 (t, J = 2.4 Hz, 1H); MS (ESI+) m/z 342.2/344.1 (M+H)+; 99.6% purity, RT 2.22 min d 4 iH NMR (CDC13, 400 MHz) 5 8.52 Prepared according (d, J = 8.0 Hz, 1H), 7.78 (s, 1H), to the method for 1 ^o- Br 7.72 (d, J = 16.0 Hz, 1H), 7.60 - starting from 2- (£)-/V-(2-hi'omophcnyl)(3- 7.56 (m, 1H), 7.38 - 7.34 (m, 1H), bromoaniline methoxy(propyn-l - 7.19 - 7.16 (m, 1H), 7.12-7.11 (m, yloxy)phenyl)acrylamide 1H), 7.07 - 6.98 (m, 2H), 6.48 (d, J =16.0 Hz, 1H), 4.82 (d, J = 4.0 Hz, 2H), 3.96 (s, 3H), 2.55 (t, J = 4.0 Hz, 1H); MS (ESI+) m/z 386.1/388.1 (M+H)+; 96.3% purity, RT 2.18 min (Method 10) 1H NMR (DMSO-d6, 400MHz) 5 0 Prepared according .0. 9.37 (s, 1H), 7.52 (d, J = 15.6 Hz, to the method for 1 ^O' 1H), 7.25 (d, /= 10.8 Hz, 1H), 7.22 starting from o- (3-methoxy(propyn- -7.18 (m, 4H), 7.09 - 7.07 (m, 2H), toluidine 1 -yloxy)phcnyl)-/V-(o- 6.88 (d, J= 15.6 Hz, 1H), 4.84 (d, J tolyl)acrylamide = 2.4 Hz, 2H), 3.84 (s, 3H), 3.59 (t, J = 2.4 Hz, 1H ), 2.25 (s, 3H ); MS (ESI+) m/z 322.2 (M+H)+; 100% purity, RT 2.01 min (Method 10) 6 o 1H NMR (CD3OD, 400 MHz) 5 7.40 Prepared according .0. (d, /= 8.8 Hz, 1H), 7.72 (d, /= 15.6 to the method for 1 CN Hz, 1H), 7.68 - 7.66 (m, 2H), 7.36 - starting from 2- (£)-/V-(2-cyanophcnyl)(3- 7.34 (m, 1H), 7.27 - 7.26 (m, 1H), aminobenzonitrile methoxy(propyn-l - 7.20 - 7.19 (m, 1H), 7.11 - 7.09 (m, yloxy)phenyl)acrylamide 1H), 6.80 (d, /= 15.6 Hz, 1H), 4.81 (d, 7=2.4 Hz, 2H), 3.91 (s, 3H), 2.98 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 333.2 ; 96.7% purity, RT 1.92 min (Method 10) 7 06* 1H NMR (DMSO-dg, 400 MHz) 5 Prepared according .44 (s, 1H), 8.11 (d, 7 = 1.2 Hz, to the method for 1 1H), 7.60 - 7.55 (m, 3H), 7.26 - 7.25 starting from 3, 4- (m, 1H), 7.20 (d, 7 = 8.4 Hz, 1H), dichloroaniline (£’)-/V-(3,4-dichloi'ophcnyl)(3- 7.09 (d, 7 = 8.4 Hz, 1H), 6.67 (d, 7 = y(propyn-l - 15.6 Hz, 1H), 4.84 (d, 7 = 2.0 Hz, yloxy)phenyl)acrylamide 2H), 3.84 (s, 3H), 3.59 (t, 7=2.0 Hz, 1H); MS (ESI+) m/z 376.1/378.1/380.1 (M+H)+; 95.8% purity, RT 2.4 min (Method 10) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-phenylacrylamide (8) .0. jO .0.
‘OH vQ H2N H To a solution of (T)(3-mcthoxypropynoxy-phcnyl)propcnoic acid (0.1 g, 0.431 mmol, 1.0 equiv.) and HATU (0.327 g, 0.861 mmol, 2.0 equiv.) in N,N- dimethylformamide (2 mL) was added ropylethylamine (015 mL, 0.861 mmol, 2.0 equiv.) and the mixture was stirred at 30 °C for 1 hour. Then aniline (59 pL, 0.646 mmol, 1.5 equiv.) was added and the reaction was stirred at 30 °C for another 2 hours. The reaction liquid was diluted with methanol (3 mL) and the resulting e was purified by ative HPLC to give the desired product as a yellow solid (25 mg, 19%); ^ NMR (DMSO-Je, 400 MHz) 8 10.14 (s, 1H), 7.72 - 7.69 (m, 2H), 7.54 (d, /= 16.0 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.26 - 7.25 (m, 1H), 7.24 - 7.23 (m, 1H), 7.10 - 7.04 (m, 2H), 6.73 (d, / = 15.6 Hz, 1H), 4.85 (d, / = 2.4 Hz, 2H), 3.85 (s, 3H), 3.60 (t, / = 2.4 Hz, 1H). MS (ESI+) m/z 308.1 (M+H)+; 100% purity, RT 2.94 min (Method 11).
Ex Structure Data Method 9 o *H NMR (400 MHz, CDC13): d, Prepared ing N ppm 7.68 (1H, d, J = 15.3 Hz), 7.32 to the method for 8 ^0 .0^ - 7.24 (2H, m), 7.26 (2H, s), 7.22 - starting from (E) 7.16 (2H, m), 7.06 (2H, dd, J = 1.8, 0 (3-methoxyprop- 8.3 Hz), 7.08 - 6.98 (2H, m), 7.00 2-ynoxymethyl (£T)-l-(3-(3-methoxy- (2H, d, J = 8.3 Hz), 6.96 - 6.95 (1H, phenyl)prop 4-(propyn-l- m), 6.68 (1H, d, J = 15.8 Hz), 4.79 enoic acid and yloxy)phenyl)acryloyl)- (2H, d, J = 2.3 Hz), 4.22 - 4.14 (1H, methyl 1,2,3,4- 1,2,3,4-tetrahydroquinoline- m), 3.90 - 3.85 (4H, m), 3.85 - 3.77 tetrahydroquinoline 4-carboxylate (1H, m), 3.73 - 3.72 (3H, m), 2.53 - boxylate 2.51 (1H, m), 2.47 - 2.37 (1H, m), 2.23 - 2.13 (1H, m). MS: (ESI+) m/z 406(M+H)+ 97.74% purity, RT = 3.33min., d 2)._________ O *H NMR (400 MHz, CDC13): d, Prepared according .0. ppm 7.68 (1H, d, J = 16.2 Hz), 7.24 to the method for 8 -7.11 (4H, m), 7.08 - 6.94 (3H, m), starting from (E) 6.74 (1H, d, J = 15.8 Hz), 4.78 (2H, (3-methoxyprop- d, J = 2.5 Hz), 3.95 - 3.90 (2H, m), 2-ynoxy- (E)-\ -(3,4-dihydroquinolin- 3.85 (3H, s), 2.79 - 2.74 (2H, m), phenyl)prop 1 (2//)-yl)(3-methoxy 2.53 - 2.51 (1H, m), 2.06 - 1.97 (2H, enoic acid and (propyn-l- m). MS: (ESI+) m/z 348.2(M+H)+ 1,2,3,4- phenyl)propen-1 - 99.45% , RT = 3.47min., tetrahydroquinoline one d 2)._____________________ 11 O 1HNMR(400MHz, CDC13): d, Prepared according .0. rY ppm 7.69 (1H, d, J = 14.9 Hz), 7.11 to the method for 8 k/NH - 6.98 (5H, m), 6.92 (1H, d, J = 15.3 starting from (E) Hz), 6.68 - 6.63 (2H, m), 4.79 (2H, (3-methoxyprop- d, J = 2.5 Hz), 4.16 - 4.07 (1H, m), 2-ynoxy- (E)-\ -(3,4-dihydroquinoxalin- 4.02 - 3.97 (2H, m), 3.86 (3H, s), )prop 1 (2/7) -yl) -3 -(3 -methoxy 3.54 - 3.50 (2H, m), 2.53 - 2.51 (1H, enoic acid and (propyn-l- m). MS: (ESI+) m/z 349(M+H)+ 1,2,3,4- yloxy)phenyl)propen-1 - 92.91% purity, RT = 3.23min., tetrahydroquinoxali one (Method 2)._____________________ ne 12 O Prepared according .0. N"> 1HNMR(400MHz, CDC13): d, to the method for 8 ppm 7.73 (1H, d, J = 15.3 Hz), 7.22 starting from (E) - 7.15 (1H, m), 7.14 - 7.08 (2H, m), (3-methoxyprop- 7.05 - 6.99 (2H, m), 6.98 - 6.87 (3H, 2-ynoxy- (£)-1 -(2,3 -dihydro-4H- m), 4.80 (2H, d, J = 2.3 Hz), 4.39 - phenyl)prop benzofb] [ 1,4]oxazinyl) 4.35 (2H, m), 4.10 - 4.06 (2H, m), enoic acid and 3,4- (3-methoxy(propyn-l - 3.88 (3H, s), 2.54 - 2.52 (1H, m). dihydro-2H- yloxy)phenyl)propen-1 - MS: (ESI+) m/z 350(M+H)+ 99% benzofb] [1,4] oxazi one purity, RT = 3.39min., d 2). ne 13 O ‘H NMR (400 MHz, Prepared according CDC13) 7.51 (1H, d, J=15.4 Hz), to the method for 8 H NH2 7.10 - 7.07 (1H, m), 7.06 - 7.02 (1H, starting from (E) m), 6.97 (1H, d, J=8.3 Hz), 6.41 (3-methoxyprop- (1H, d, J=14.9 Hz), 6.00 - 5.93 (1H, 2-ynoxy- (E)-N-((trans) m), 4.78 (2H, d, J=2.5 Hz), 3.89 phenyl)prop aminocyclohexyl) -3 -(3 - (3H, s), 3.77 - 3.66 (1H, m), 2.68 - enoic acid and methoxy(propyn-l - 2.59 (1H, m), 2.54 - 2.51 (1H, m), treins-c yc I oh c x an c - phenyl) acrylamide 2.01 - 1.96 (2H, m), 1.77 - 1.66 (2H, 1,2-diamine m), 1.33 - 1.19 (4H, m); MS: (ESI+) m/z 329.2(M+H)+ 99.01% purity, RT = 2.87min., (Method 3). 14 /°' 0 1^ ‘H NMR (400 MHz, Prepared according % DMSO) 5 7.59(d,/= 15.7 Hz, to the method for ^0' 'OH 1H), 7.54 (d, J= 6.9 Hz, 1H), 7.34 - 16 starting from (£T)-l-(4-hydroxy-3,4- 7.29 (m, 2H), 7.28 - 7.17 (m, 3H), (£)(3-mcthoxydihydroquinolin-1 (2//)-yl) 7.09 (d, J= 8.6 Hz, 1H), 6.92 (d, J = pyn-l- (3-methoxy(propyn-l - 15.7 Hz, 1H), 5.54 (d, J= 5.6 Hz, yloxy)phenyl) acryli yloxy)phenyl)propen-1 - 1H), 4.87 (d, J= 2.3 Hz, 2H), 4.70 - c acid and 1,2,3,4- one 4.64 (m, 1H), 4.13 - 4.05 (m, 1H), tetrahydroquinolin- 3.83 (s, 3H), 3.76 - 3.67 (m, 1H), 4-ol 3.63 (t, J= 2.3 Hz, 1H), 2.23 - 2.13 (m, 1H), 1.90 - 1.80 (m, 1H). MS (ESI+) m/z 364.2 (M+H)+; 99.8% purity, RT 3.06 min (Method 2) /°' o ‘H NMR (400 MHz, Prepared according N DMSO) 5 12.21 - 12.16 (m, 1H), to the method for OH 8.46 (d, J= 8.3 Hz, 1H), 7.87 (d, J = 16 starting from {E)-\ -(3-hydroxy-1 zol- 6.6 Hz, 2H), 7.74 - 7.69 (m, 2H), (£)(3-mcthoxyyl) -3 -(3 -methoxy(prop- 7.49.7.43 (m, 2H), 7.39 (dd, J = 4-(propyn-l- 2-yn-1 -yloxy)phenyl)prop 8.3 Hz, J= 1.8 Hz, 1H), 7.18 (d, J = yloxy)phenyl) acryli en-l-one 8.6 Hz, 1H), 4.93 (d, /= 2.3 Hz, c acid and 3- 2H), 3.92 (s, 3H), 3.66 (t, J= 2.3 indazolinone Hz, 1H); MS (ESI+) m/z 349.3 (M+H)+; 98.9% purity, RT 2.60 min (Method 3) (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide o o .0. .0.
'OH h2n N Nx N N ^ N \ // HN-N HN-N To a solution of (T)(3-mcthoxy(propyn-l -yloxyjphcnyl(acrylic acid (0.1 g, 0.431 mmol, 1.0 ) and 2-(2H-tetrazolyl)aniline (0.083 g, 0.516 mmol, 1.2 equiv.) in dichloromethane (3 mL) were added A^iV-diisopropylcthylaminc (0.225 mL, 1.29 mmol, 3.0 equiv.) and HATU (0.245 g, 0.645 mmol, 1.5 equiv.). The reaction mixture was stirred at 25°C for 16 hours and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the desired product as a light yellow solid (0.025 g, 15%); ^ NMR r/e, ) 5 12.45 (br. s., 1H), 8.71 - 7.65 (m, 1H), 7.19 (dd, /i = 8.0 Hz, J2=2.0 Hz, 1H), 7.63 (d,/= 15.6 Hz, 1H), 7.38 - 7.25 (m, 3H), 7.16 - 7.08 (m, 3H), 6.75 (d,/= 15.6 Hz, 1H), 4.85 (d, /= 2.0 Hz, 2H), 3.88 (s, 3H), 3.61 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 398.1 (M+Na)+; 95.9% purity, RT 1.95 min (Method 10).
(E)-N-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (17) a) ((E)-N-(2-(N-hydroxycarbamimidoyl)phenyl)(3-methoxy(propyn-l- phenyl) -acrylamide vO o .0. .0.
H H HN NH N \ To a solution of (£,)-/V-(2-cyanophenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide (1.00 g, 3.01 mmol, 1.0 equiv.) (6) and hydroxylamine hydrochloride (0.418 g, 6.02 mmol, 2.0 equiv.) in ethanol (13 mL) was added a solution of sodium bicarbonate (0.505 g, 6.02 mmol, 2.0 equiv.) in water (2 mL) and the mixture was stirred at 80 °C for 12 hours. The mixture was cooled to 20 °C and concentrated under d pressure to give a e, which was dissolved in dichloromethane/ethanol (20/1, 200 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was triturated in dichloromethane/methanol (50/1, 40 mL) to give the desired product as a light yellow solid. (0.6 g, 69%); MS (ESI+) m/z 366.1 (M+H)+. b) (/?)-/V-(2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide o o .0. .0.
N N H H HN\ NH 1ST N OH b-U To a suspension of ((L)-A/-(2-(A/-hydroxycarbamimidoyl)phcnyl)(3-mcthoxy (propyn-l-yloxy)phenyl)acrylamide (0.08 g, 0.218 mmol, 1.0 ) in trimethoxymethane (2.91 g, 27.4 mmol, 3 mL, 125 ) was added ylbenzenesulfonic acid (0.004 g, 0.022 mmol, 0.1 equiv.) and the mixture stirred at 100 °C for 12 hours. The mixture was concentrated under reduced pressure to give a residue, which was triturated with methanol (2 mL) and the solid collected by filtration to give the desired product as a light yellow solid (0.045 g, 52%); H 1 NMR (DMSO-de, 400MHz) 5 10.07 (br. s., 1H), 9.81 (s, 1H), 8.24 (d, /= 8.0 Hz, 1H), 8.03 (d, / = 8.0 Hz, 1H), 7.61 - 7.59 (m, 1H), 7.56 (d, / = 15.6 Hz, 1H), 7.34 - 7.33 (m, 2H), 7.2 (d, / = 8.4 Hz, 1H), 7.08 (d, / = 8.4 Hz, 1H), 6.80 (d, / = 15.6 Hz, 1H), 4.85 (d, / = 2.0 Hz, 2H), 3.82 (s, 3H), 3.60 (t, /= 2.0 Hz, 1H); MS (ESI+) m/z 398.2 (M+Na)+; 94.4% purity, RT 2.18 min (Method 10). (/?)(3-methoxy( propyn-l -yloxy)phenyl)-N-(2-(5-methyl-l ,2,4-oxadiazol yl)phenyl)-acrylamide (18) o O .0. .0.
N N H H HN\ NH N ^ NK To a solution of ((T)-A/-(2-(A/-hydroxycarbamimidoyl)phcnyl)(3-mcthoxy(prop- 2-yn-l-yloxy)phenyl)acrylamide (0.1 g, 0.273 mmol, 1.0 equiv.) in toluene (1 mL) and pyridine (1 mL) was added acetyl de (0.043 g, 0.547 mmol, 2.0 equiv.) and the mixture was stirred at 20°C for 30 minutes, then heated to 110 °C for 12 hours. The e was concentrated under reduced pressure to give a residue, which was triturated in methanol (2 mL) and the solid collected by filtration to give the desired product as a light yellow solid (0.042 g, 38%); ^ NMR (DMSO-de, 400 MHz) 5 10.18 (s, 1H), 8.36 (d, 7= 7.6 Hz, 1H), 8.02 (d, /= 7.6 Hz, 1H), 7.61 -7.56 (m, 2H), 7.35 - 7.24 (m, 3H), 7.08 (d, 7=8.0 Hz, 1H), 6.81 (d, 7= 16.0 Hz, 1H), 4.85 (d, 7 = 2.0 Hz, 2H), 3.85 (s, 3H), 3.60 (t, 7 = 2.0 Hz, 1H), 2.73 (s, 3H); MS (ESI+) m/z 390.1 (M+H)+; 95.5% purity, RT 2.95 min (Method 8). (/?)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-l,2,4-oxadiazol yl)phenyl)acrylamide (19) o o .0. N N H HN\ NH To a suspension of ((L)-A/-(2-(A/-hydroxycarbamimidoyl)phcnyl)(3-mcthoxy (propyn-l-yloxy)phenyl)acrylamide (0.120 g, 0.328 mmol, 1.0 equiv.) in l (2.5 mL) was added sodium methoxide (0.213 g, 0.985 mol, 25%, 3.0 equiv.) and yl carbonate (110 pL, 1.31 mmol, 4.0 equiv.). The mixture was stirred at 90 °C for 15 hours, cooled to 20 °C and filtered. The filtrate was concentrated under reduced re and the residue was purified by preparative HPLC to give the desired product as a light yellow solid (0.020 g, 15%); ^ NMR (DMSO-76, 400 MHz) 5 10.63 (br. s., 1H), 8.23 (d, 7= 8.0 Hz, 1H), 7.71 (d, 7= 8.0 Hz, 1H), 7.59 - 7.52 (m, 2H), 7.30 (s, 1H), 7.27 - 7.22 (m, 2H), 7.08 (d, 7 = 8.0 Hz, 1H), 6.71 (d, 7 = 16.0 Hz, 1H), 4.85 (d, 7 = 2.0 Hz, 2H), 3.84 (s, 3H), 3.59 (t, 7 = 2.0 Hz, 1H); MS (ESI+) m/z 414.1 (M+Na)+; 96.4% purity, RT 1.59 min (Method 8). (2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-lyloxy )phenyl)acrylamide (20) a) (E)-N-((dimethylamino)methylene)nitrobenzamide o2n o2n O-^ nh2 To the solution of obenzamide (1.4 g, 8.43 mmol, 1.0 equiv.) was added N,N- dimethylformamide dimethyl acetal (5.02 g, 42.1 mmol, 5.0 equiv.) and the reaction mixture was stirred at 120 °C for 2 hours. The mixture was concentrated under d pressure and the residue purified by silica gel chromatography leum ether: ethyl acetate = 10:1 to 1:1) to afford ddi methyl ami no) mcthylcnc)nitrobcnzamidc as a yellow solid (1.20 g crude) which was used without further purification. MS (ESI+) m/z 222.1 (M+H)+. b) 5-(2-nitrophenyl)-l,2,4-oxadiazole o2n o2n O N N O VN To a on of hydroxylamine hydrochloride (0.98 g, 14.1 mmol, 1.3 equiv.) in sodium hydroxide (5 M, 2.8 mL, 1.3 ) was added (E)-N- (dimethylaminomethylene)nitrobenzamide (2.4 g, 10.8 mmol, 1.0 equiv.) portion-wise over 5 minutes at 20 °C and the mixture stirred at 20 °C for 0.5 hour. The mixture was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic layer was dried and concentrated under reduced pressure to give (L)-A/-((hydroxyamino)mcthylcnc) nitrobenzamide (1.20 g) which was used directly without further purification.
A mixture of (E)-N-((hydroxyamino)methylene)nitrobenzamide (0.9 g, 4.30 mmol, 1.0 equiv.) in acetic acid (7 mL) and dioxane (7 mL) was stirred at 90 °C for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum ethenethyl acetate 10:1 to 5:1) to give the desired product as a light yellow solid (0.4 g, 49%); 1H NMR (DMSO-d6, 400 MHz) 5 9.25 (s, 1H), 8.23 - 8.21 (m, 1H), 8.13 - 7.11 (m, 1H), 7.99 - 7.95 (m, 2H). c) 2-(l,2,4-oxadiazolyl)aniline o2n h2n 0 nN 0 nN To a solution of 5-(2-nitrophenyl)-l,2,4-oxadiazole (0.3 g, 1.57 mmol, 1.0 equiv.) in l (5 mL) was added tin(II) chloride ate (1.42 g, 6.28 mmol, 4.0 equiv.) and the mixture was stirred at 90°C for 12 hours. The mixture was concentrated under d pressure and the residue was dissolved in ethyl acetate (10 mL) and washed with saturated aqueous sodium bicarbonate (5 mL) and brine (5 mL). The c layer was dried and concentrated under reduced pressure and the residue was purified by silica gel chromatography (petroleum thyl acetate 1:1 to ethyl acetate) to give the desired product as a light yellow solid (0.1 g, %); lR NMR (DMSO-d6, 400 MHz) 5 10.96 (s, 1H), 7.88 - 7.86 (m, 1H), 7.57 - 7.53 (m, 1H), 7.19 (d, /= 8.0 Hz, 1H), 7.11 - 7.07 (m, 1H), 6.37 (br. s., 2H); MS (ESI+) m/z 162.1 (M+H)+. d) (2-(l,2,4-oxadiazolyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide o o .0. .0.
"OH h2n N #^0 0 XN 0 To a solution of (£’)(3-methoxypropynoxy-phenyl)propenoic acid (0.056 g, 0.242 mmol, 1.0 equiv.) and 2-(l,2,4-oxadiazolyl)aniline (0.039 g, 0.242 mmol, 1.0 ) in pyridine (2 mL) was added phosphorus oxychloride (0.037 g, 0.242 mmol, 1.0 equiv.) at 0°C and the mixture was stirred at 20°C for 12 hours. The mixture was quenched with water (1 mL), diluted with ethyl acetate (20 mL) and washed with IN hydrochloric acid (20 mL) and then saturated aqueous sodium bicarbonate (5 mL). The organic layer was dried and concentrated under reduced pressure to give a residue, which was triturated in methanol (3 mL) and the solid collected by filtration to give the desired product as a light yellow solid (4 mg, 5%); iH NMR (DMSO-de, 400 MHz) 5 12.23 (s, 1H), 11.69 (s, 1H), 8.06 (d, /= 7.6 Hz, 1H), 7.79 - 7.72 (m, 2H), 7.51 (d, /= 8.0 Hz, 1H), 7.40 (t, /= 8.0 Hz, 1H), 7.27 - 7.25 (m, 2H), 7.12 (d, / = 8.0 Hz, 1H), 6.86 (d, / = 16.0 Hz, 1H), 4.86 (d, / = 2.0 Hz, 2H), 3.83 (s, 3H), 3.61 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 376.3 ; 100% purity, RT 1.97 min (Method 10).
Ex Structure Data Method 21 o iH NMR (DMSO-d6, 400 MHz) 5 ed according N 10.71 (s, 1H), 9.44 (s, 1H), 8.47 (d, to the method for ^'o N'' 0 / = 8.0 Hz, 1H), 7.98 (d, / = 8.0 Hz, 20 (step d) starting N=^ 1H), 7.66 (d, /= 8.0 Hz, 1H), 7.61 from 2-(l,3,4- (E)-N-(2-( 1,3,4-oxadiazol (d, J= 16.0 Hz, 1H), 7.39 (d, J= 2.4 oxadiazol yl)phenyl)(3-methoxy(prop- Hz, 1H), 7.36 - 7.32 (m, 1H), 7.27 line and (£)- 2-yn-1 -yloxy)phenyl)acrylamide (d, /= 8.0 Hz, 1H), 7.08 (d, /= 8.0 3-(3-methoxy Hz, 1H), 6.63 (d, / = 16.0 Hz, 1H), propynoxy- 4.86 (d, /= 2.0 Hz, 2H), 3.86 (s, )prop 3H), 3.60 (t, J = 2.0 Hz, 1H); MS enoic acid (ESI+) m/z 398.1 (M+Na)+; 98.9% purity, RT 2.71 min d 8) (/?)(3-methoxy(propyn-l-yloxy)phenyl)-/V-(2-(l-methyl-lH-pyrazolyl)phenyl)- acrylamide (22) a) (E)(4-hydroxymethoxyphenyl)-N-(2-(l-methyl-lH-pyrazolyl)phenyl)acrylamide O B" .0. .0. N N H Br // HO' // A mixture of (£’)-A/-(2-bromophenyl)(3-methoxypropynoxy-phenyl)prop enamide (0.16 g, 0.414 mmol, 1.0 equiv.) (4), (l-methylpyrazolyl)boronic acid (0.104 g, 0.828 mmol, 2.0 equiv.), [l,r-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.03 g, 0.041 mmol, 0.1 equiv.) and sodium carbonate (0.131 g, 1.24 mmol, 3.0 equiv.) in dioxane (6 mL) and water (1 mL) was stirred at 80 °C for 24 hours under nitrogen. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether:ethyl acetate 1:1) to give the title compound as light yellow gum (0.1 g, 19%); MS (ESI+) m/z 350.2 (M+H)+. b) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-methyl-lH-pyrazol nyl)acryl-amide o o .0. .0.
N N H H HO' // y' N-N N-N / / A mixture of (£)(4-hydroxymcthoxy-phcnyl)-A/-[2-(l-mcthylpyrazol yl)phenyl]propenamide (0.1 g, 0.286 mmol, 1.0 equiv.), 3-bromoprop-l-yne (0.068 g, 0.572 mmol, 2.0 equiv.) and potassium carbonate (0.119 g, 0.858 mmol, 3.0 equiv.) in acetone (5 mL) was stirred at 20 °C for 12 hours. The mixture was filtered and the filtrate was trated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired t as a light yellow solid (7 mg, 6%); ^ NMR (CDCI3, 400 MHz) 8 8.36 (hr. s., 1H), 7.71 - 7.68 (m, 2H), 7.54 (s, 1H), 7.45 (s, 1H), 7.39 - 7.34 (m, 1H), 7.29 - 7.28 (m, 1H), 7.19 - 7.17 (m, 1H), 7.13 - 7.11 (m, 1H), 7.08 - 7.06 (m, 1H), 7.03 (d, /= 8.0 Hz, 1H), 6.32 (d, J = 16.0 Hz, 1H), 4.82 (d, / = 2.4 Hz, 2H), 4.02 (s, 3H), 3.93 (s, 3H), 2.54 (t, / = 2.4 Hz, 1H); MS (ESI+) m/z 388.1 (M+H)+; 95.1% purity, RT 2.88 min (Method 11). (/?)(3-methoxy(propyn-l-yloxy)phenyl)-/V-(2-(3-methyl-lH-l,2,4-triazol-lyl l)acryl-amide (23) o H .0.
•O. .NU N H <\ P H A Br N i ;,n A mixture of (£’)-A-(2-bromophenyl)(3-methoxypropynoxy-phenyl)prop enamide (0.2 g, 0.517 mmol, 1.0 equiv.) (4), yl1,2,4-triazole (0.258 g, 3.11 mmol, 6.0 equiv.), cuprous iodide (0.049 g, 0.258 mmol, 0.5 ) and cesium carbonate (0.506 g, 1.55 mmol, 3.0 equiv.) in dimethyl sulfoxide (2 mL) was stirred at 100 °C under nitrogen in microwave for 3 hours. The mixture was cooled to 25°C, diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired product as a light yellow solid (5 mg, 2%); ^ NMR (CDCI3, 400 MHz) 5 9.89 (s, 1H), 8.63 (d, /= 8.0 Hz, 1H), 8.37 (s, 1H), 7.64 (d, /= 16.0 Hz, 1H), 7.46 (t, /= 8.0 Hz, 1H), 7.35 (d, /= 8.0 Hz, 1H), 7.21 (t, /= 8.0 Hz, 1H), 7.15 (d, / = 8.0 Hz, 1H), 7.08 - 7.05 (m, 2H), 6.36 (d, /= 16.0 Hz, 1H), 4.82 (d, /= 2.0 Hz, 2H), 3.94 (s, 3H), 2.60 (s, 3H), 2.55 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 389.1 (M+H)+; 99% , RT 2.34 min (Method 8).
(/?)-/V-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-l-yloxy)phenyl)acrylamide ^0 IP // a) 4,4,5,5-tetramethyl(2-nitrophenyl)-l,3,2-dioxaborolane o2n o' 'o A mixture of l-bromonitro-benzene (10.0 g, 49.5 mmol, 1.0 equiv.), 4,4,5,5- tetramethyl(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-l,3,2-dioxaborolane (15.08 g, 59.4 mmol, 1.2 equiv.), potassium acetate (14.57 g, 148 mmol, 3.0 equiv.) and [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium(II) (1.09 g, 1.49 mmol, 0.03 equiv.) in e (180 mL) was stirred at 80 °C for 12 hours under nitrogen. The mixture was trated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 100:1 to 80:1) to give the desired product as yellow oil (12.0 g, 97%); NMR (DMSO-d6, 400 MHz) 5 8.17 (d, /= 8.0 Hz, 1H), 7.67 - 7.65 (m, 1H), 7.58 - 7.54 (m, 2H), 1.44 (s, 12H). b) 4-(2-nitrophenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazole o2n o2n o' "o II SEIvf A mixture of 2-[(4-bromopyrazol-l-yl)methoxy]ethyl-trimethylsilane (0.8 g, 2.89 mmol, 1.0 equiv.), 4,4,5,5-tetramethyl(2-nitrophenyl)-l,3,2-dioxaborolane (2.16 g, 8.67 mmol, 3.0 equiv.), is(diphenylphosphino)ferrocene]dichloropalladium(II) (0.211 g, 0.289 mmol, 0.1 equiv.) and potassium phosphate tribasic (1.84 g, 8.67 mmol, 3.0 equiv.) in dioxane (20 mL) and water (2 mL) was stirred at 100 °C for 12 hours under nitrogen. The mixture was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 30:1 to 15:1) to give the desired product as light yellow gum (0.16 g, 16%); NMR , 400 MHz) 5 7.76 - 7.74 (m, 2H), 7.67 (s, 1H), 7.60 - 7.56 (m, 1H), 7.52 - 7.49 (m, 1H), 7.44 - 7.40 (m, 1H), 5.46 (s, 2H), 3.61 (t,J= 8.0 Hz, 2H), 0.94 (t, J = 8.0 Hz, 2H), 0.00 (s, 9H). c) 2-(l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolyl)aniline o2n h2n II // N-N N-N SEWf SEWf To a solution of trimethyl-[2-[[4-(2-nitrophenyl)pyrazol-l-yl]methoxy] ethyl] silane (0.16 g, 0.500 mmol, 1.0 equiv.) in methanol (10 mL) was added Pd/C (0.05 g, 5% purity) and the mixture was stirred at 20 °C under a hydrogen atmosphere for 1.5 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give the desired product as light yellow gum, which was used directly without further purification (0.15 g); MS (ESI+) m/z 290.1 (M+H)+. d) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(l-((2- (trimethylsilyl)ethoxy)methyl)-lH-pyrazolyl)phenyl)acrylamide O .0.
O H2N N 'OH H ‘7’ H S’ H N-N N-N SEIvf SEIvf ] The title compound was prepared according to the ure bed for the synthesis of (1) starting from (E)(3-methoxypropynoxy-phenyl)propenoic acid and 2- (l-((2-(trimethylsilyl)ethoxy)methyl)-lH-pyrazolyl)aniline. MS (ESI+) m/z 504.2 (M+H)+. e) (E)-N-(2-(lH-pyrazolyl)phenyl)(3-methoxy(propyn-l- yloxy)phenyl)acrylamide N .o.
H N N-N H SEWf HN-N ] To a solution of (£,)(3-methoxypropynoxy-phenyl)-/V-[2-[l-(2- trimethylsilylethoxymethyl)pyrazolyl]phenyl]propenamide (0.09 g, 0.178 mmol, 1.0 equiv.) in ol (2 mL) was added 4M hydrogen chloride in methanol (6 mL) solution and the e was stirred at 20 °C for 5 hours. The mixture was concentrated under d re to give a residue which was purified by preparative HPLC to give the desired product as an off-white solid (8 mg, 12%); NMR (CDC13, 400 MHz) 5 8.40 (hr. s., 1H), 7.80 (s, 2H), 8.69 (d, /= 16.0 Hz, 1H), 7.40 - 7.32 (m, 3H), 7.21 - 7.18 (m, 1H), 7.13 - 7.10 (m, 1H), 7.08 - 7.06 (m, 1H), 7.03 (d, /= 8.0 Hz, 1H), 6.30 (d, /= 16.0 Hz, 1H), 4.81 (d, /= 4.0 Hz, 2H), 3.93 (s, 3H), 2.54 (t, / = 2.0 Hz, 1H); MS (ESI+) m/z 374.1 (M+H)+; 98.7% purity, RT 2.28 min (Method 8).
Ex Structure Data Method o iH NMR (DMSO-dg, 400 MHz) 5 Prepared according s°- NH 12.83 (s, 1H), 12.59 (hr. s„ 1H), to the method for <0^0 ^ N 8.57 (d, /= 8.0 Hz, 1H), 8.01 (s, 24 starting from 4- NHJ 1H), 7.79 - 7.74 (m, 2H), 7.58 (d, J bromo-l-((2- (E)-N-(2-( 1 H-imidazol = 8.0 Hz, 1H), 7.35 (s, 1H), 7.27 - (trimethylsilyl)etho yl)phenyl)(3-methoxy(prop- 7.19 (m, 2H), 7.08 - 7.05 (m, 2H), xy)methyl)-lH- 2-yn-1 -yloxy)phenyl)acrylamide 6.68 (d, J= 16.0 Hz, 1H), 4.85 (d, J i midazole = 2.4 Hz, 2H), 3.85 (s, 3H), 3.59 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 374.1 (M+H)+; 93.6% purity, RT 2.48 min (Method 8) 26 o 1H NMR (DMSO-d6, 400 MHz) 5 Prepared according NH 12.64 (s, 1H), 8.56 (d, J = 8.0 Hz, to the method for #^0' ^ N 1H), 7.94 (s, 1H), 7.76 (s, 1H), 7.67 24 starting from 4- / (d, /= 8.0 Hz, 1H), 7.57 (d,/= 16.0 bromo-1 l- (E)(3-methoxy(propyn- Hz, 1H), 7.35 (s, 1H), 7.26 - 7.20 IH-imidazole 1 -yloxy)phenyl)-/V-(2-( 1 -methyl- (m, 2H), 7.09 - 7.05 (m, 2H), 6.68 lH-imidazol (d, /= 16.0 Hz, 1H), 4.84 (d,/=2.0 yl)phenyl)acrylamide Hz, 2H), 3.86 (s, 3H), 3.76 (s, 3H), 3.58 (t, /= 2.0 Hz, 1H); MS (ESI+) m/z 388.1 (M+H)+; 95.5% purity, RT 2.72 min (Method 8) (E)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-N- (methylsulfonyl)benzamide (27) 0 .0. .0. N N H H O NH ^^0 O OH 0s,k To a solution of 2-[[(E)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (0.08 g, 0.227 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was added IJ'-carbonyldiimidazole (0.074 g, 0.455 mmol, 2.0 equiv.). The mixture was stirred at 50°C for 1 hour and then a solution of methanesulfonamide (0.043 g, 0.455 mmol, 2.0 equiv.) and 1,8- diazabicyclo[5.4.0]undecene (0.103 g, 0.683 mmol, 3.0 ) in tetrahydrofuran (5 mL) was slowly added. The reaction was stirred for r 5 hours at 20°C. The reaction mixture was diluted with ethyl acetate (5 mL) and washed with water (5 mL x 3). The organic layers were dried and concentrated under reduced pressure to give a residue which was purified by preparative HPLC to give the desired t as a white solid (20 mg, 21%); 1H NMR (DMSO- d6, 400 MHz) 5 10.74 (br. s., 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.2 Hz, 1H), 7.58 - 7.56 (m, 2H), 7.33 (s, 1H), 7.22 - 7.21 (m, 2H), 7.08 - 7.06 (m, 1H), 6.77 (d, J = 16.0 Hz, 1H), 4.84 (d, J = 2.0 Hz, 2H), 3.84 (s, 3H), 3.59 (t, J = 2.0 Hz, 1H), 3.32 (s, 3H); MS (ESI+) m/z 451.1 +; 98% purity, RT 2.81 min (Method 11).
(E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)phenyl)acryl-amide (28) a) N-((E)-l-(hydroxyimino)ethyl)((E)(3-methoxy(propyn-l- phenyl)acrylamido)-benzamide o o o o N N H H Xnoh ^0 O' OH O' NH To a solution of 2-[[(E)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (0.1 g, 0.284 mmol, 1.0 equiv.) in N,N-dimethylformamide (5 mL) was added HATU (0.129 g, 341 umol, 1.2 equiv.), N,N-diisopropylethylamine (0.110 g, 0.853 mmol, 3.0 equiv.) and N-hydroxyacetamidine (0.042 g, 0.569 mmol, 2.0 equiv.) and the mixture stirred for 12 hours at 25 °C. The reaction mixture was filtered and concentrated to give a residue which was purified by silica gel tography (petroleum ether: ethyl acetate 5:1 to ethyl acetate) to give the desired product as a light yellow solid and used without further purification (0.15 g crude); 1H NMR (CDC13, 400 MHz) 5 11.33 (s, 1H), 8.86 (d, J = 8.4 Hz, 1H), 7.99- 7.96 (m, 1H), 7.66 (d, J = 15.2 Hz, 1H), 7.59 - 7.58 (m, 1H), 7.12 - 7.07 (m, 3H), 7.03 (d, J = 8.8 Hz, 1H), 6.49 (d, J = 15.2 Hz, 1H), 4.81 (d, J = 2.0 Hz, 2H), 3.95 (s, 3H), 2.54 (t, J = 2.0 Hz, 1H), 2.15 (s, 3H). b) (E)(3-methoxy(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-l,2,4-oxadiazol yl)pheny 1) -acrylamide o o .0. N N Xnoh H CT NH A solution of N-((E)-l-(hydroxyimino)ethyl)((E)(3-methoxy(propyn-l- phenyl)-acrylamido)benzamide (0.15 g, 0.368 mmol, 1.0 equiv.) in N,N- dimethylformamide (3 mL) was heated to 110 °C for 10 hours. The reaction mixture was ed and the filtrate was concentrated under d pressure to give a residue which was purified by ative HPLC to give the desired product as a light yellow solid (10 mg, 21%); 1H NMR (DMSO-d6, 400 MHz) 5 11.39 (s, 1H), 8.97 (d, J = 8.0 Hz, 1H), 8.13 (d, J = 8.4 Hz, 1H), 7.75 (d, J = 15.6 Hz, 1H), 7.63 (t, J = 8.4 Hz, 1H), 7.26 - 7.25 (m, 2H), 7.14 (s, 1H), 7.09 (d, J = 8.8 Hz, 1H), 6.53 (d, J = 15.6 Hz, 1H), 4.83 (d, J = 2.0 Hz, 2H), 3.96 (s, 3H), 2.58 (s, 3 H), 2.56 (t, J = 2.0 Hz, 1H); MS (ESI+) m/z 412.1 (M+Na)+; 93% purity, RT 3.33 min (Method 11). (/?)(3-methoxy(propyn-l-yloxy)phenyl)-/V-(2-(5-methyl-l,3,4-oxadiazol yl)phenyl)-acrylamide (29) /O. N N H H Nr 'o To a solution of ’)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoic acid (0.5 g, 1.42 mmol, 1.0 equiv.) in acetonitrile (30 mL) was added acetohydrazide (0.126 g, 1.70 mmol, 1.2 equiv.) and phosphorus oxychloride (1.09 g, 7.10 mmol, .0 equiv.). The reaction mixture was stirred at 106°C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford the desired product as a yellow solid (28 mg, 5%); ^ NMR (DMSO-Je, 400 MHz) 8 11.04 (s, 1H), 8.12 (d, 7=8.0 Hz, 1H), 7.97 (d,/= 16.0 Hz, 1H), 7.88 - 7.86 (m, 1H), 7.73 ( d, / = 8.0 Hz, 1H), 7.53 (t, / = 8.0 Hz, 1H), 7.37 - 7.36 (m, 2H), 7.14 - 7.10 (m, 2H), 4.87 (d, / = 2.0 Hz, 2H), 3.86 (s, 3H), 3.34 (t, / = 2.0 Hz, 1H), 2.19 (s, 3 H); MS (ESI+) m/z 390.1 (M+H)+; 95.5% , RT 1.77 min (Method 10).
(/?)-/V-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn lyloxy) ) acrylamido) benzamide (30) o o .0. .0.
N N H H O' O OH O' To a solution of A/',A/'-dimethylethane-1,2-diamine (42.9 mg, 0.487 mmol, 1.5 equiv.) in dichloromethane (5 mL) was added ’)(3-methoxypropynoxy-phenyl)prop enoyl]amino]benzoyl chloride (120 mg, 0.325 mmol, 1.0 equiv.) (prepared from 2-[[(£’)(3- methoxypropynoxy-phenyl)propenoyl]amino]benzoic acid and thionyl chloride) and triethylamine (99 mg, 0.974 mmol, 3.0 equiv.) and the resulting mixture was stirred at 20°C for 12 hrs. The reaction e was filtered and the filtrate was concentrated under reduced pressure to give a residue which was purified by preparative HPLC to afford the title compound as a light yellow solid as the trifluoroacetic acid salt (27.8 mg, 19%); H NMR (CDCI3, 400 MHz) 12.45 (br. s., 1H), 11.63 (s, 1H), 8.87 (br. s., 1H), 8.76 (d, /= 8.4 Hz, 1H), 8.02 (d, /= 8.0 Hz, 1H), 7.68 (d, /= 15.6 Hz, 1H), 7.52 (t, /= 8.4 Hz, 1H), .12 (m, 3H), 7.02 (d, /= 8.4 Hz, 1H), 6.50 (d, /= 16.0 Hz, 1H), 4.82 (s, 2H), 3.95 (s, 3H), 3.91 (br. s., 2H), 3.31 (br. s., 2H) 2.91 (s, 6H), 2.55 (s, 1H); MS (ESI+) m/z 422.2 (M+H)+; 93.7% purity, RT 2.46 min (Method 11).
Ex Structure Data Method 31 fi' 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared N 16.00 (br. s. 1H), 12.45 (br. s., 1H), according to the O' NH 10.37 (s, 1H), 7.90 (d, J = 6.4 Hz, method for 1 N^N 1H), 7.78 (d, / = 6.4 Hz, 1H), 7.59 t u starting from 2- HN-N (t, J= 7.6 Hz, 1H), 7.52 (d, /= 15.6 (£)(3-(3-mcthoxy(propyn- amino-/V-(2HHz , 1H), 7.28 - 7.26 (m, 2H), 7.19 yloxy)phenyl)acrylamido)-/V- tetrazol 7.18 (m, 1H), 7.07 (d, /= 18.4 Hz, trazolyl)benzamide yl)benzamide (J. 1H), 6.72 (d, /= 15.6 Hz, 1H), 4.84 Med. Chem. (d, J = 2.0 Hz, 2H), 3.83 (s, 3H), 1986,29, 2403) 3.34 (t, /= 2.0 Hz, 1H); MS (ESI+) m/z 419.0 (M+H)+; 97% purity, RT 2.73 min (Method 11) 32 o iH NMR , 400 MHz) 5 Prepared N 12.73 (br. s„ 1H), 11.68 (s, 1H), according to the O' O' N N 8.76 (d, /= 8.4 Hz, 1H), 8.07 (br. method for 30 H I s„ 1H), 7.80 (d, J= 8.0 Hz, 1H), starting from N,N- /V-(3-(dimethylamino)propyl)(3- 7.69 (d, /= 15.6 Hz, 1H), 7.53 - dimethylpropane- (3-methoxy(propyn-1 - 7.52 (m, 1H), 7.16 - 7.13 (m, 3H), amine yloxy)phenyl)acrylamido) 7.03 (d, /= 8.0 Hz, 1H), 6.50 (d, J benzamide trifluoroacetic acid salt = 15.6 Hz, 1H), 4.81 (s, 2H), 3.95 (s, 3H), 3.59 (d, J= 5.6 Hz, 2H), 3.17 (t, J= 6.8 Hz, 2H), 2.85 (s, 6H), 2.55 (s, 1H), 2.19 (t, J= 6.0 Hz, 2H); MS (ESI+) m/z 436.2 (M+H)+; 96.4% purity, RT 2.45 min (Method 11) 33 o 1 H NMR (DMSO, 400 MHz) ed N 511.46 (s, 1H), 8.81 (d, 7=5.2 Hz, according to the O' O' N 1H), 8.54 (d, 7= 8.4 Hz, 1H), 7.75 method for 30 H (d, 7 =8.4 Hz, 1H), 7.56-7.51 (m, starting from 2- (£T)(3-(3-methoxy(propyn- 2H), 7.41 (d, 7=1.2 Hz, 1H), 7.24 methoxyethanamin l-yloxy)phenyl)acrylamido)-/V-(2- (d, 7= 8.8 Hz, 1H), 7.17 - 7.15 (m, e methoxyethyl)benzamide 1H), 7.05 (d, 7= 8.4 Hz, 1H), 6.78 (d, 7= 15.6 Hz, 1H), 4.84 (s, 2H), 3.85 (s, 3H), 3.59 (s, 1H), 3.50- 3.40 (m, 4H), 3.28 (s, 3H); MS (ESI+) m/z 409.2 (M+H)+; 96.9% purity, RT 2.93 min (Method 11) 34 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared N 11.34 (s, 1H), 8.81 (br. s, 1H), 8.49 according to the H r? O' O' N (d, 7= 8.4 Hz, 1H), 7.75 (d, 7= 7.2 method for 30 H Hz, 1H), 7.57 - 7.52 (m, 2H), 7.40 starting from 2-(4- (s, 1H), 7.24 (d, 7= 8.0 Hz, 1H), (£T)(3-(3-methoxy(propyn- methylpiperazin-1 - 7.18 (t, 7= 8.0 Hz, 1H), 7.06 (d, 7 = l-yloxy)phenyl)acrylamido)-/V-(2- yl)ethanamine 8.4 Hz, 1H), 6.77 (d, 7= 15.6 Hz, (4-methylpiperazin-1 - 1H), 5.40-4.20 (m, 6H), 3.85 (s, yl)ethyl)benzamide trifluoroacetic 3H), 3.59 (s, 1H), 3.54-3.52 (m, acid salt 2H), 3.50 - 2.99 (m, 4H), 2.94 - 2.92 (m, 2H), 2.76 (s, 3H); MS (ESI+) m/z 477.2 ; 97% purity, RT 2.38 min (Method 11) o 1H NMR (CDCI3, 400 MHz) 5 ed N r? 11.56 (s„ 1H), 8.76 (d, 7= 8.0 Hz, according to the H o^n^n^ O' 1H), 8.55 (br. s, 1H), 8.71 - 7.67 method for 30 H (m, 2H), 7.52 (t, 7= 4.0 Hz, 1H), starting from 2- (£T)(3-(3-methoxy(propyn- 7.15 - 7.12 (m, 3H), 7.04 (d, 7= 8.0 morpholinoethana l-yloxy)phenyl)acrylamido)-/V-(2- Hz, 1H), 6.48 (d, 7= 15.2 Hz, 1H), mine morpholino ethyl)benzamide 4.82 (d, 7 = 2.0 Hz, 2H), 4.02 - 4.01 trifluoroacetic acid salt (m, 4H), 3.95 (s„ 3H), 3.91 (d, 7 = 4.8 Hz, 2H), 3.70 - 3.50 (m, 2H), 3.36 (d, 7=4.8 Hz, 2H), 3.10 - 2.80 (m, 2H), 2.55 (s, 1H). MS (ESI+) m/z 464.2 (M+H)+; 94.2% purity, RT 2.47 min (Method 11) 36 iH NMR (DMSO-d6, 400 MHz) 5 Prepared 11.21 (s, 1H), 9.56 (br. s, 1H), 8.75 according to the (d, J= 7.2 Hz, 1H), 8.45 (d, J= 8.0 method for 30 H Hz, 1H), 7.75 (d, J= 7.6 Hz, 1H), ng from 1- (£T)(3-(3-methoxy(propyn- 7.56 - 7.52 (m, 2H), 7.39 (s„ 1H), methylpiperidin 1-yloxy)phenyl)acrylamido)-/V-( 1 - 7.23 (d, /= 8.0 Hz, 1H), 7.18 (t, / = amine methylpiperidinyl)benzamide 8.0 Hz, 1H), 7.06 (d, J= 8.4 Hz, trifluoroacetic acid salt 1H), 6.76 (d, /= 15.6 Hz, 1H), 4.85 (s, 2H), 4.05 - 4.02 (m, 1H), 3.85 (s, 3H), 3.69 (s, 1H), 3.60-3.58 (m, 2H), 3.12 - 3.07 (m, 2H), 2.78 (d, J= 3.6 Hz, 3H), 2.08 - 2.05 (m, 2H), 1.80- 1.74 (m, 2H); MS (ESI+) m/z 448.2 (M+H)+; 99% , RT 2.47 min (Method 11) 37 o iH NMR d6, 400 MHz) 5 Prepared N 11.39 (s, 1H), 9.46 (br. s, 1H), 8.87 according to the O' H O (t, 7=5.2 Hz, 1H), 8.51 (d, 7=8.0 method for 30 Hz, 1H), 7.77 (d, 7= 7.2 Hz, 1H), starting from (1- (£T)(3-(3-methoxy(propyn- 7.56 - 7.52 (m, 2H), 7.41 (s, 1H), methylpiperidin 1 -yloxy)phenyl)acrylamido)-/V-(( 1 - 7.24 (d, 7= 8.0 Hz, 1H), 7.19 (t, 7 = yl)methanamine methylpiperidin 7.6 Hz, 1H), 7.06 (d, 7= 8.4 Hz, yl)methyl)benzamide 1H), 6.77 (d, 7= 15.6 Hz, 1H), 4.85 trifluoroacetic acid salt (s, 2H), 3.85 (s, 3H), 3.59 (s, 1H), 3.44- 3.41 (m, 2H), 3.21 (t, 7= 5.6 Hz, 2H), 2.94 - 2.85 (m, 2H), 2.74 (d, 7= 4.4 Hz, 3H), 1.90 (d,7 = 14.4 Hz, 2H), 1.87-1.82 (m, 1H), 1.44- 1.38 (m, 2H); MS (ESI+) m/z 462.2 (M+H)+; 98.9% purity, RT 2.49 min (Method 11) 38 o iH NMR (DMSO-d6, 400 MHz) 5 Prepared /O' N I X? 11.21 (s, 1H), 9.38 (d, 7= 6.4 H, according to the O' 1H), 8.50 (d, 7= 7.6 Hz, 1H), 7.83 method for 30 H (d, 7= 1.2 Hz. 1H), 7.55-7.51 (m, starting from (£T)(3-(3-methoxy(propyn- 2H), 7.40 (d, 7= 2.0 Hz, 1H), 7.23 oxetanamine 1 )phenyl)acrylamido)-/V- -7.19 (m, 2H), 7.05 (d, 7 = 8.4 Hz, (oxetan-3 -yl)benzamide 1H), 6.78 (d, 7= 15.6 Hz, 1H), 5.05 - 5.02 (m, 1H), 4.84 (d, 7 = 2.4 Hz, 2H), 4.78 (t, 7 = 6.8 Hz, 2H), 4.63 (d, 7= 6.4 Hz, 2H), 3.85 (s, 3H), 3.59 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 407.2 (M+H)+; 98.4% purity, RT 1.82 min (Method 10) 39 o iH NMR (DMSO-dg, 400 MHz) 5 Prepared NH’ 11.30 (s, 1H), 8.75 (d, 7= 8.4 Hz, ing to the 0‘ O' NH 1H), 7.77 (d, 7= 15.2 Hz, 1H), 7.55 method for 30 - 7.45 (m, 2H), 7.14 - 7.09 (m, 3H), starting from ^-o 7.03 (d, 7= 8.8 Hz, 1H), 6.58 (br. s, (tetrahydrofuran- (£T)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-/V- 1H), 6.49 (d, /= 15.6 Hz, 1H), 4.81 3-yl)methanamine ((tetr ahydrofuran-3 - (d, /= 2.4 Hz, 2H), 4.00-3.95 (m, yl)methyl)benzamide 4H), 3.85-3.78 (m, 1H), 3.80-3.74 (m, 1H), 3.70-3.67 (d, /= 4.4 Hz, 1H), 3.55 - 3.44 (m, 2H), 2.70-2.60 (m, 1H), 2.54 (t, /= 2.4 Hz, 1H), 2.17 - 2.12 (m, 1H), 1.73 - 1.70 (m, 1H); MS (ESI+) m/z 435.3 ; 99.2% purity, RT 1.92 min d 10)_______________ 40 iH NMR (DMSO-d6, 400 MHz) 5 Prepared NH / 11.11 (s, 1H), 9.23 (t, 7=5.2 Hz, according to the 0' 0 1H), 9.01 (s, 1H), 8.38 (d, 7= 7.6 method for 30 & ^-N Hz, 1H), 7.75 (d, 7= 8.0 Hz, 1H), starting from (1- (£T)(3-(3-methoxy(propyn- 7.65 (s, 1H), 7.54 - 7.50 (m, 2H), methyl-lHyloxy)phenyl)acrylamido)-/V-(( 1 - 7.37 (d, 7=2.0 Hz, 1H), 7.23-7.19 ol methyl-1 H-imidazol-5 - (m, 2H), 7.07 (d, 7= 8.4 Hz, 1H), yl)methanamine yl)methyl)benzamide 6.75 (d, 7=15.6 Hz, 1H), 4.85 (d, 7 oroacetic acid salt = 2.4 Hz, 2H), 4.59 (d, 7= 2.0 Hz, 2H), 3.88 (s, 3H), 3.85 (s, 3H) 3.60 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 445.3 (M+H)+; 96.3% purity, RT 1.54 min (Method 10) 41 o iH NMR (DMSO-d6, 400 MHz) 5 Prepared .0. 11.35 (s, 1H), 9.39 (d, 7= 6.0 Hz, according to the O' 0 1H), 8.59 (hr. s, 1H), 8.52 (d,7 = method for 30 8.4 Hz, 1H), 7.89-7.87 (m, 2H), starting from (£T)(3-(3-methoxy(propyn- .51 (m, 3H), 7.38-7.37 (m, pyridin 1 -yloxy)phenyl)acrylamido)-/V- 2H), 7.21 (d, 7= 8.4 Hz, 2H), 7.04 ylmethanamine (pyridinylmethyl)benzamide (d, 7= 8.4 Hz, 1H), 6.75 (d,7 = .6 Hz, 1H), 4.83 (d, 7= 2.4 Hz, 2H), 4.65 (d, 7= 5.6 Hz, 2H), 3.83 (s, 3H), 3.57 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 442.2 (M+H)+; 97.6% purity, RT 1.59 min (Method 10) 42 iH NMR (CDC13, 400 MHz) 5 0 Prepared .0. % 11.59 (s, 1H), 8.78 (d, 7= 8.4 Hz, according to the O’ 0 ff Sj 1H), 8.60 (s, 1H), 8.00 (hr. s, 1H), method for 30 7.70 - 7.67 (m, 2H), 7.65 - 7.53 (m, starting from 2- (£T)(3-(3-methoxy(propyn- 2H), 7.24 - 7.22 (m, 2H), 7.17 - (pyridin l-yloxy)phenyl)acrylamido)-/V-(2- 7.10 (m, 3H), 7.03 (d, 7= 8.4 Hz, yl)ethanamine (pyridinyl)ethyl)benzamide 1H), 6.51 (d, 7= 15.6 Hz, 1H), 4.81 (d, 7= 1.6 Hz, 2H), 3.96 (s, 3H), 3.89 - 3.85 (m, 2H), 3.13 (t, 7= 6.0 Hz, 2H), 2.55 (t, 7= 2.4 Hz, 1H); MS (ESI+) m/z 456.2 (M+H)+; 98.2% purity, RT 2.86 min (Method 13) 43 0 iH NMR (DMSO-d6, 400 MHz) 5 Prepared .0. 11.27 (s, 1H), 9.42 (br. s, 1H), 8.81 according to the a 0 "'"O (br. s, 1H), 8.69 (br. s, 1H), 8.46 (d, method for 30 J = 8.4 Hz, 1H), 8.24 (br. s, 1H), starting from (£T)(3-(3-methoxy(propyn- 7.84 (d, /= 7.6 Hz, 1H), 7.55 (br. s, pyridin 1 -yloxy)phenyl)acrylamido)-/V- 1H), 7.55 - 7.50 (m, 2H), 7.39 (s, ylmethanamine (pyridinylmethyl)benzamide 1H), 7.23 - 7.21 (m, 2H), 7.06 (d, J trifluoroacetic acid salt = 8.4 Hz, 1H), 6.76 (d, J= 15.6 Hz, 1H), 4.85 (d, /= 2.4 Hz, 2H), 4.63 (d, J= 4.0 Hz, 2H), 3.85 (s, 3H), 3.60 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 442.1 (M+H)+; 99.2% purity, RT 1.49 min (Method 10) 44 iH NMR (CDC13, 400 MHz) 5 Prepared .62 (s, 1H), 9.09 (s, 1H), 8.64 (d, according to the /= 6.4 Hz, 2H), 8.46 -8.45 (m, 1H), method for 30 7.78 - 7.73 (m, 3H), 7.56 - 7.55 (m, starting from (£T)(3-(3-methoxy(propyn- 1H), 7.36 - 7.35 (m, 1H), 7.25 - namine 1 -yloxy)phenyl)acrylamido)-/V- 7.24 (m, 1H), 7.20 (s, 1H), 7.15 (s, (pyridinyl)benzamide 1H), 7.09 - 7.01 (m, 1H), 6.45 (d, J = 15.6 Hz, 1H), 4.83 (d, J= 2.4 Hz, 2H), 3.98 (s, 3H), 2.56 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 428.1 (M+H)+; 96.3% purity, RT 2.44 min (Method 8) 45 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared N H u 11.24 (s, 1H), 9.48 (t, 7=6.0 Hz, ing to the O' 1H), 8.72 (d, 7= 6.0 Hz, 2H), 8.46 method for 30 (d, 7= 8.0 Hz, 1H), 7.89 (d, 7= 6.8 starting from (£T)(3-(3-methoxy(propyn- Hz, 1H), 7.76 (d, J = 6.0, 2H), 7.55 pyridin 1 -yloxy)phenyl)acrylamido)-/V- - 7.51 (m, 2H), 7.37 (d, 7= 1.6 Hz, ylmethanamine (pyridinylmethyl)benzamide 1H), 7.23 - 7.20 (m, 2H), 7.04 (d, 7 trifuoroacetic acid salt = 8.4 Hz, 1H), 6.74 (d, 7= 15.6 Hz, 1H), 4.83 (d, 7= 2.4 Hz, 2H), 4.68 (d, 7= 5.6 Hz, 2H), 3.83 (s, 3H), 3.59 (t, 7 = 2.4 Hz, 1H); MS (ESI+) m/z 442.1 (M+H)+; 98.7% purity, RT 2.5 min d 11) 46 1H NMR <4 400 MHz) 5 0 Prepared N 11.31 (s, 1H), 8.94-8.93 (m, 1H), according to the O' O' 8.81 (d, 7= 6.4 Hz, 2H), 8.54 (d, 7 method for 30 = 8.0 Hz, 1H), 7.89 (d, 7= 6.4 Hz, starting from 2- (£T)(3-(3-methoxy(propyn- 2H), 7.72 (d, 7= 7.6 Hz, 1H), 7.62- in l-yloxy)phenyl)acrylamido)-/V-(2- 7.58 (m, 2H), 7.47 (d, 7= 1.2 Hz, yl)ethanamine (pyridinyl)ethyl)benzamide 1H), 7.37-7.33 (m, 1H), 7.24-7.21 (m, 1H), 7.12 (d, 7= 8.4 Hz, 1H), 6.81 (d, 7= 15.6 Hz, 1H), 4.90 (d, 7 = 2.0 Hz, 2H), 3.92 (s, 3H), 3.76- 3.70 (m, 2H), 3.65 (s, 1H), 3.18 (t, 7 = 6.4 Hz, 2H); MS (ESI+) m/z 456.2 (M+H)+; 95.1% purity, RT 1.54 min d 10) 47 o iH NMR (DMSO-<4, 400 MHz) 5 Prepared .0. 11.07 (s, 1H), 10.67 (s, 1H), 8.47 ing to the O' W" (d, J= 7.2 Hz, 1H), 8.04 (s, 1H), method for 30 H 7.82 (d, /= 6.8 Hz, 1H), 7.62 (s, starting from 1- (£T)(3-(3-methoxy(propyn- 1H), 7.60 - 7.52 (m, 2H), 7.39 (d, J methyl-lH- 1-yloxy)phenyl)acrylamido)-/V-( 1 - = 2.0 Hz , 1H), 7.24 - 7.23 (m, 2H), pyrazolamine methyl-1 H-pyrazolyl)benzamide 7.06 (d, /= 8.0 Hz, 1H), 6.79 (d, J = 15.6 Hz, 1H), 4.84 (d, J= 2.4 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.59 (t, J= 2.4 Hz, 1H); MS (ESI+) m/z 431.1 (M+H)+; 96.3% purity, RT 2.62 min (Method 12) 48 o iH NMR (DMSO-dg, 400 MHz) 5 Prepared N T l==\ H 1 L N 10.98 (s, 1H), 10.93 (s, 1H), 8.42 according to the O' o^n-^n (d, 7=8.0 Hz, 1H), 7.86 (d, 7=8.0 method for 30 H Hz, 1H), 7.64 (d, 7= 2.0 Hz, 1H), ng from 1- (£T)(3-(3-methoxy(propyn- 7.56 - 7.52 (m , 2H), 7.40 (s, 1H), methyl-lHyloxy)phcnyl)acrylamido)-/V-( 1 - 7.23 - 7.18 (m, 2H), 7.05 (d, 7= 8.4 pyrazolamine methyl-1 H-pyrazol-3 -yl)benzamide Hz, 1H), 6.83 (d, 7=15.6 Hz, 1H), 6.60 (s, 1H), 4.84 (s, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 3.58 (s, 1H); MS (ESI+) m/z 431.2 (M+H)+; 94% purity, RT 1.93 min (Method 10) (/?)(3-(3-methoxy(propyn-l-yloxy)phenyl)acrylamido)-/V-(piperidinyl)benzamide N NH O' OH To a solution of 2-[[(£’)(3-methoxypropynoxy-phenyl)prop amino]benzoic acid (100 mg, 0.285 mmol, 1.0 equiv.), / O. N N H H OH HO' O^ OH HN5X° A mixture of 2-[[(T)(4-hydroxymcthoxy-phcnyl)propcnoyl]amino]benzoic acid (150 mg, 0.479 mmol, 1.0 equiv. Bioorg. Med. Chem. Lett. 2009, 19, 7003-7006), tertbutyl 4-(p-tolylsulfonyloxymethyl)piperidine-l-carboxylate (265 mg, 0.718 mmol, 1.5 equiv.) and potassium hydroxide (0.5 M, 3.8 mL, 4.0 ) in acetone (3 mL) was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure and the residue stirred in 4M en chloride in dioxane (10 mL). The solvent was d in vacuo and the residue purified by preparative HPLC to give the desired product as a yellow solid as the trifluoroacetic acid salt (60.5 mg, 26.6%); ^ NMR (DMSO-d6, 400 MHz) 6 11.32 (s, 1H), .60 (m, 2H), 8.32 (br. s, 1H), 8.02 (dd, /= 8.0 Hz, /= 1.2 Hz, 1H), 7.62 (t, /= 8.0 Hz, 1H), 7.57(d, /= 15.6 Hz, 1H), 7.40 (d, /= 1.6 Hz, 1H), 7.25 (d, /= 8.0 Hz, 1H), 7.18 (t, /= 8.0 Hz, 1H), 7.03 (d, / = 8.4 Hz, 1H), 6.81 (d, /= 15.6 Hz, 1H), 3.92 (d, /= 6.4 Hz, 2H), 3.88 (s, 3H), 3.20 - 3.35 (m, 2H), 2.85 - 3.00 (m, 2H), 2.00 - 2.20 (m, 1H), 1.80 - 2.00 (m, 2H), 1.40 - 1.55 (m, 2H); MS (ESI+) m/z 411.2 (M+H)+; 90.3% , RT 2.16 min (Method 11). (/?)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid I o 'O' 0 OH a) l-methylpyrrolidinyl 4-methylbenzenesulfonate Crm %rCr / O'0* To the solution of l-methylpyrrolidinol (300 mg, 2.97 mmol, 1.00 equiv) and potassium ide (666 mg, 11.86 mmol, 4.00 equiv) in tetrahydrofuran (5 mL) was added 4-methylbenzenesulfonyl chloride (848 mg, 4.45 mmol, 1.50 equiv) portion-wise maintaining the temperature at 0 °C and the resultant yellow slurry was stirred at 25°C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford the d product as yellow oil (523 mg, 65%) which was used t r purification; MS (ESI+) m/z 256.1 (M+H)+. b) (E)(3-(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid A. o A. 0 N N O' OH HO' O^ OH A mixture of 2-[[(T)(4-hydroxymcthoxy-phcnyl)propcnoyl]amino]benzoic acid (100 mg, 0.32 mmol, 1.00 equiv), (l-methylpyrrolidinyl) 4-methylbenzenesulfonate (130 mg, 0.48 mmol, 1.50 equiv) and potassium hydroxide (0.5 M, 2.55 mL, 4.00 equiv) in acetone (3 mL) was stirred at 60°C for 16 hours. The reaction e was concentrated in vacuo and the residue purified by preparative HPLC to afford the desired product as a light yellow solid (72 mg, 44 %) as a trifluoroacetate salt; NMR (CDCI3, 400 MHz) 5 11.48 (s, 1H), 8.87 (d, /= 8.8 Hz, 1H), 8.18 (dd, 7=8.0 Hz,/= 1.2 Hz, 1H), 7.61 -7.65 (m, 2H), 7.16 (t,/= 8.0 Hz, 1H), 7.02- 7.07 (m, 2H), 6.83 (d, /= 8.0 Hz, 1H), 6.42 (d, /= 15.6 Hz, 1H), 5.17 (s, 1H), 4.10 - 4.40 (m, 1H), 3.90 - 4.00 (m, 1H), 3.86 (s, 3H), 3.20 - 3.40 (m, 2H), 3.07 (s, 3H), 2.40 - 2.55 (m, 2H); MS (ESI+) m/z 397.3 (M+H)+; 98.8% purity; RT = 1.93 min (Method 10). (/?)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid o o O N N n/J Cl H O OH HO" O"^ OH 0 A solution of 2-[[(£)(4-hydroxymethoxy-phenyl)propenoyl] ami no] benzoic acid (100 mg, 0.32 mmol, 1.00 equiv.), 4-(chloromethyl)-3,5-dimethyl-isoxazole (87 mg, 0.48 mmol, 1.50 equiv.) and potassium hydroxide (0.5 M, 2.6 mL, 4.00 equiv.) in acetone (2 mL) was stirred at 60°C for 16 hours. The reaction e was concentrated in vacuo and the residue was purified by preparative HPLC to afford the desired product as a light yellow solid (65 mg, 47%); i H NMR (DMSO-de, 400 MHz) 5 11.28 (s, 1H), 8.62 (d, /= 8.4 Hz, 1H), 8.01 (d, /= 8.0 Hz, 1H), 7.62 (t, / = 8.0 Hz, 1H), 7.57 (d, / = 15.2 Hz, 1H), 7.39 (s, 1H), 7.28 (d, / = 8.0 Hz, 1H), 7.17 (t, 7 = 7.6 Hz, 1H), 7.12 (d, 7=8.4 Hz, 1H), 6.81 (d, 7 =15.6 Hz, 1H), 4.95 (s, 2H), 3.83 (s, 3H), 2.39 (s, 3H), 2.21 (s, 3H); MS (ESI+) m/z 423.1 (M+H)+; 98.2% purity; RT = 1.49 min (Method 1). (/?)(3-(3-methoxy((l-methyl-l//-pyrazolyl)methoxy)phenyl)acrylamido)benzoic add (53) NfjP° cr oh a) 3-methoxy((l-methyl-lH-pyrazolyl)methoxy)benzaldehyde ;xr° Ex Structure Data Method 54 iH NMR (DMSO-d6, 400 MHz) 5 I o Prepared H 11.29 (s, 1H), 8.63 (d, /= 8.4 Hz, according to the O^OH 1H), 8.01 (d, /= 6.4 Hz, 1H), 7.61 method for 51 (E)(3-(3 -methoxy(oxetan-3 - (t,/= 10.0 Hz, 1H), 7.57 (d, / = starting from 2- ylmethoxy)phenyl)acrylamido)ben 15.6 Hz, 1H), 7.38 (d, J= 2.0 Hz, [[(£)(4- zoic acid 1H), 7.25 (d, /= 8.4 Hz, 1H), 7.17 hydroxy (t, / = 8.0 Hz, 1H), 7.05 (d, / = 8.4 methoxy- Hz, 1H), 6.80 (d, J= 15.6 Hz, 1H), )prop 4.71 (dd, J= 8.0 Hz, J= 6.0 Hz, enoyl] amino] benz 2H), 4.41 (t, J= 6.0 Hz, 2H), 4.24 oic acid and (d, J= 6.8 Hz, 2H), 3.84 (s, 3H), oxetan 3.30 - 3.40 (m, 1H); MS (ESI+) m/z ylmethanol 384.1 (M+H)+; 97.7% purity, RT 2.86 min (Method 12) 55 1H NMR (DMSO-d6, 400 MHz) 5 I o Prepared (X0- H 11.19 (s, 1H), 8.62 (d, /= 8.4 Hz, according to the O-'tDH 1H), 8.58 (d, /= 4.4 Hz, 1H), 8.00 method for 51 (dd, J= 7.2 Hz, J = 2.0 Hz, 1H), starting from 2- (£T)(3-(3-methoxy(pyridin 7.85 (t, J= 7.6 Hz, 1H), 7.61 (t, / = ylmethoxy)phenyl)acrylamido)ben 3-(4- 7.6 Hz, 1H), 7.56 (d, J= 15.6 Hz, zoic acid hydrochloric acid salt hydroxy 1H), 7.52 (d, /= 7.6 Hz, 1H), 7.42 methoxy-_____ WO 44620 (d, /= 2.0 Hz, 1H), 7.36 (dd, J= phenyl)prop 7.2 Hz, J = 4.2 Hz, 1H), 7.23 (dd, J enoyl] amino] benz = 8.4 Hz, /= 1.2 Hz, 1H), 7.17 (t,/ oic acid and = 8.0 Hz, 1H), 7.07 (d, J= 8.4 Hz, pyridine 1H), 6.80 (d, /= 15.6 Hz, 1H), 5.22 ylmethanol (s, 2H), 3.88 (s, 3H); MS (ESI+) m/z 405.1 (M+H)+; 95.8% purity, RT 2.63 min (Method 11)_________ 56 I o iH NMR (DMSO-dg, 400 MHz) 5 Prepared 0 % N 11.28 (s, 1H), 8.62 (d, /= 8.0 Hz, according to the Sr H "O' O^OH 1H), 8.55 (d, /= 3.6 Hz, 1H), 8.00 method for 51 (£T)(3-(3-methoxy(2-(pyridin- (dd, 7=7.6 Hz,/= 1.2 Hz, 1H), starting from 2- 2- 7.81 (t, 7= 7.2 Hz, 1H), 7.61 (t, 7 = [[(£)(4- yl)ethoxy)phenyl)acrylamido)benz 8.0 Hz, 1H), 7.56 (d, 7= 15.6 Hz, hydroxy oic acid trifluoroacetic acid salt 1H), 7.45 (d, 7= 7.6 Hz, 1H), 7.37 methoxy- (d, 7= 1.2 Hz, 1H), 7.31(dd, 7= 6.4 phenyl)prop Hz, 7= 5.2 Hz, 1H), 7.24 (dd, 7= enoyl] amino] benz 8.8 Hz, 7= 1.2 Hz, 1H), 7.17 (t, 7 = oic acid and 2- 7.6 Hz, 1H), 7.05 (d, 7= 8.4 Hz, (pyridin 1H), 6.79 (d, 7= 15.6 Hz, 1H), 4.40 yl)ethan-l-ol (t, 7= 6.8 Hz, 2H), 3.80 (s, 3H), 3.24 (t, 7= 6.8 Hz, 2H); MS (ESI+) m/z 419.1 ; 93.9% purity, RT 2.49 min (Method 11) 57 I o iH NMR (DMSO-dg, 400 MHz) 5 Prepared 0 % 11.28 (s, 1H), 8.64 - 8.60 (m, 2H), according to the 'O' O-'XJH 8.52 (d, 7= 4.0 Hz, 1H), 8.00 (dd, 7 method for 51 (£T)(3-(3-methoxy(2-(pyridin- = 7.6 Hz, 7= 1.2 Hz, 1H), 7.94 (d, starting from 2- 3- 7= 7.6 Hz, 1H), 7.61 (t, 7= 8.4 Hz, [[(£)(4- yl)ethoxy)phenyl)acrylamido)benz 1H), 7.56 (d, 7= 15.6 Hz, 1H), 7.49 hydroxy oic acid trifluoroacetic acid salt (dd, 7= 7.6 Hz, 7= 4.8 Hz, 1H), methoxy- 7.38 (d, 7= 2.0 Hz, 1H), 7.23(dd, 7 phenyl)prop = 8.0 Hz, 7= 2.0 Hz, 1H), 7.17 (t, 7 enoyl] amino] benz = 7.6 Hz, 1H), 7.03 (d, 7= 8.8 Hz, oic acid and 2- 1H), 6.80 (d, 7= 15.6 Hz, 1H), 4.27 (pyridin (t, 7= 6.8 Hz, 2H), 3.82 (s, 3H), an-l-ol 3.12 (t, 7= 6.8 Hz, 2H); MS (ESI+) m/z 419.3 (M+H)+; 99.1% purity, RT 1.61 min (Method 10) 58 o i H NMR (DMSO-dg, 400 Prepared MHz) 5 11.30 (s, 1H), 8.75 (d, 7 = according to the O^OH 6.4 Hz, 2H), 8.64 (d, 7= 7.6 Hz, method for 51 1H), 8.02 (d, 7= 6.4 Hz, 1H), 7.71 starting from 2- (£T)(3-(3-methoxy(pyridin (d, 7= 6.4 Hz, 2H), 7.62 (t, 7= 8.4 3-(4- ylmethoxy)phenyl)acrylamido)ben Hz, 1H), 7.57 (d, 7= 15.6 Hz, 1H), hydroxy zoic acid trifluoroacetic acid salt 7.46 (d, 7= 1.2 Hz, 1H), 7.25 (d, 7 methoxy- = 8.4 Hz, 1H), 7.17 (t, 7= 7.6 Hz, phenyl)prop 1H), 7.06 (d, 7= 8.4 Hz, 1H), 6.83 enoyl] amino] benz (d, 7= 15.6 Hz, 1H), 5.38 (s, 2H), oic acid and 3.91 (s, 3H); MS (ESI+) m/z 405.3 pyridin ; 99.6% purity, RT 1.99 WO 44620 min (Method 10) ylmethanol 59 I o iH NMR (DMSO-d6, 400 MHz) 5 Prepared 0 % 11.28 (s, 1H), 8.78 (d, /= 6.4 Hz, according to the 0 O^OH 2H), 8.63 (d, /= 8.0 Hz, 1H), 8.01 method for 51 (£T)(3-(3-methoxy(2-(pyridin- (d, J= 8.0 Hz, 1H), 7.89 (d, J = 6.4 ng from 2- 4- Hz, 2H), 7.62 (t, J= 8.0 Hz, 1H), [[(£)(4- yl)ethoxy)phenyl)acrylamido)benz 7.56 (d, /= 15.6 Hz, 1H), 7.39 (d, J hydroxy oic acid trifluoroacetic acid salt = 1.2 Hz, 1H), 7.25 (d, J = 8.4 Hz, methoxy- 1H), 7.17 (t, / = 7.6 Hz, 1H), 7.06 phenyl)prop (d, 7=8.4 Hz, 1H), 6.80 (d,/ = enoyl] amino] benz .6 Hz, 1H), 4.38 (t, 7= 6.4 Hz, oic acid and 2- 2H), 3.82 (s, 3H), 3.32 (t, 7= 6.0 (pyridin Hz, 2H); MS (ESI+) m/z 419.1 yl)ethan-l-ol (M+H)+; 98.8% purity, RT 2.49 min (Method 11) 60 iH NMR (DMSO-dg, 400 MHz) 5 Prepared 11.74 (hr. s, 1H), 8.64 (d,7=9.2 according to the cr° Cr OH Hz, 1H), 8.02 (d, 7= 7.2 Hz, 1H), method for 52 N'N 7.55-7.59 (m, 2H), 7.38-7.41 (m, starting from 2- (£)(3-(3 -methoxy(( 1 -methyl- 2H), 7.24 - 7.27 (m, 1H), 7.15-7.18 [[(£)(4- lH-pyrazol (m, 2H), 6.80 (d, 7= 15.2 Hz, 1H), hydroxy yl)methoxy)phenyl)acrylamido)ben 6.38 (s, 1H), 5.21 (s, 2H), 3.85 (s, methoxyzoic 3H); MS (ESI+) m/z 408.3 phenyl)prop (M+H)+; 95.9% purity, RT 1.94 enoyl] amino] benz min (Method 10) oic acid and 5- omethyl) -1 - methyl-1H- pyrazole________ 61 iH NMR (CDC13, 400 MHz) 5 Prepared v. 11.23 (s, 1H), 8.86 (d, 7= 8.4 Hz, according to the ‘OH 1H), 8.13 (d, 7= 8.0 Hz, 1H), 7.67 method for 52 (£)(3-(4-mcthoxy(2- (d, 7= 15.6 Hz, 1H), 7.63 (t, 7= 7.6 ng from (E)- methoxy ethoxy )phenyl) acrylamide Hz, 1H), 7.16 - 7.10 (m, 3H), 6.83 2-(3-(3-hydroxy )benzoic acid (d, 7= 8.4 Hz, 1H), 6.41 (d, 7 = yphenyl) ac .2 Hz, 1H), 4.25 (t, 7= 4.4 Hz, rylamido)benzoic 2H), 3.87 (t, 7= 4.8 Hz, 2H), 3.82 acid and 1-bromo- (s, 3H), 3.51 (s, 3H); MS (ESI+) 2-methoxyethane m/z 372.1 (M+H)+; 99% purity, RT 2.9 min (Method 11) 62 1H NMR (CD3OD, 400 MHz) 5 0 Prepared N 8.74 (d, 7= 5.2 Hz, 1H), 8.69 (d, 7 according to the 'O' 0^ OH = 8.4 Hz, 1H), 8.44 (t, 7= 8.0 Hz, method for 51 (E)(3 -(4-methoxy-3 -(2-(pyridin- 1H), 8.12 (d, 7= 7.6 Hz, 1H), 8.03 starting from 2- 2- (d, 7= 8.0 Hz, 1H), 7.86 (t, 7 = 6.4 [[(E)- (£)(3-(3- yl)ethoxy)phenyl)acrylamido)benz Hz, 1H), 7.62 - 7.56 (m, 2H), 7.27 - hydroxy oic acid trifluoroacetic acid salt 7.24 (m, 2H), 7.17 (t, 7= 7.6 Hz, methoxyphenyl) ac 1H), 6.98 (d, 7= 8.0 Hz, 1H), 6.60 rylamido)benzoic (d, 7= 15.6 Hz, 1H), 4.48 (t, 7= 5.2 acid and 2- Hz, 2H), 3.81 (s, 3H), 3.52 (t, 7 = (pyridin 4.8 Hz, 2H); MS (ESI+) m/z 419.2 yl)ethan-l-ol_____ (M+H)+; 95.1% purity, RT 2.52 min (Method 11)____________ 63 i nO^Q- 0 H NMR (CD3OD, 400 MHz) 5 Prepared N 8.95 (s, 1H), 8.78 (d,/=5.6Hz, according to the 'O' 0"X)H 1H), 8.71 (d, /= 8.4 Hz, 1H), 8.61 method for 51 (E)(3-(4-methoxy(pyridin (d, J= 8.0 Hz, 1H), 8.13 (d, J= 6.6 starting from 2- ylmethoxy)phenyl)acrylamido)ben Hz, 1H), 7.98 - 8.02 (m, 1H), 7.65 - [[(E)- (£)(3-(3- zoic acid trifluoroacetic acid salt 7.59 (m, 2H), 7.44 (d, J= 1.2 Hz, hydroxy 1H), 7.33 (d, /= 4.8 Hz, 1H), 7.17 methoxyphenyl) ac (t, J= 7.6 Hz, 1H), 7.09 (d, /= 8.4 rylamido)benzoic Hz, 1H), 6.66 (d, J= 15.6 Hz, 1H), acid and n .39 (s, 2H), 3.92 (s, 3H); MS ylmethanol (ESI+) m/z 405.1 (M+H)+; 93.4% , RT 1.54 min (Method 10) 64 1H NMR (CD3OD, 400 MHz) 5 Prepared 8.91 (s, 1H), 8.74 (d, J = 5.2 Hz, according to the 1H), 8.67 - 8.63 (m, 2H), 8.09 (dd, method for 51 (E)(3 -(4-methoxy-3 -(2-(pyridin- J= 8.0 Hz, /= 1.2 Hz, 1H), 8.02 starting from 2- 3- (dd, J= 7.6 Hz, /= 6.0 Hz, 1H), [[(E)- (E)(3-(3- yl)ethoxy)phenyl)acrylamido)benz 7.58 - 7.52 (m, 2H), 7.23 - 7.12 (m, hydroxy oic acid trifluoroacetic acid salt 3H), 6.95 (d, /= 8.4 Hz, 1H), 6.56 methoxyphenyl) ac (d, J= 15.6 Hz, 1H), 4.36 (t, J= 4.8 rylamido)benzoic Hz, 2H), 3.83 (s, 3H), 3.36 (t, J = acid and 2- 4.8 Hz, 2H); MS (ESI+) m/z 419.2 (pyridin (M+H)+; 95.3% purity, RT 2.54 yl)ethan-l-ol min d 12) 65 1H NMR (CD3OD, 400 MHz) 5 0 Prepared fi N 8.76 (d, /= 8.0 Hz, 2H), 8.70 (d, J according to the 'O' O^OH = 11.2 Hz, 1H), 8.15 - 8.05 (m, method for 51 (E)(3 -(4-methoxy-3 -(2-(pyridin- 3H), 7.63 - 7.56 (m, 2H), 7.29 (s, starting from 2- 4- 1H), 7.26 (d,/= 11.2 Hz, 1H), 7.17 [[(E)- (3-(3- yl)ethoxy)phenyl)acrylamido)benz (t, J= 7.6 Hz, 1H), 7.00 (d, / = 11.2 hydroxy oic acid oroacetic acid salt Hz, 1H), 6.63 (d, J= 16.8 Hz, 1H), methoxyphenyl) ac 4.46 (t, J= 7.6 Hz, 2H), 3.84 (s, do)benzoic 3H), 3.45 (t, J = 7.2 Hz, 2H); MS acid and 2- (ESI+) m/z 419.1 (M+H)+; 96.1% (pyridin purity, RT 2.52 min (Method 12) yl)ethan-l-ol 66 "Xo. o 1 H NMR (DMSO-d6, 400 MHz) 5 Prepared N 11.60 (hr. s, 1H), 8.63 (d,/= 8.4 according to the o OH Hz, 1H), 8.01 (d, J= 7.2 Hz, 1H), method for 53 (E)(3-(4-methoxy((l-methyl- 7.81 (s, 1H), 7.64 - 7.40 (m, 4H), starting from 3- lH-pyrazol 7.24 (t, J= 8.4 Hz, 1H), 7.15 (t, / = hydroxy yl)methoxy)phenyl)acrylamido)ben 7.6 Hz, 1H), 6.99 (t, 7=8.0 Hz, methoxybenzaldeh zoic acid 1H), 6.79 (d, 7= 15.6 Hz, 1H), 5.01 yde (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H); MS (ESI+) m/z 408.2 (M+H)+; 96.8% purity, RT 1.94 min (Method 10) 67 o iH NMR (CD3OD, 400 MHz) 5 Prepared % 8.70 (d, / = 11.2 Hz, 1H), 8.12 (d, J according to the / H "O' cr oh = 9.6 Hz, 1H), 7.66 - 7.50 (m, 2H), method for 52 (£)(3-(4-mcthoxy(( 1 -methyl- 7.45 - 7.39 (m, 2H), 7.27 (d, / = ng from 2- lH-pyrazol 10.8 Hz, 1H), 7.16 (t, /= 10.4 Hz, [[(E)- (E)(3-(3- yl)methoxy)phenyl)acrylamido)ben 1H), 7.03 (d,/= 11.2 Hz, 1H), 6.63 hydroxy zoic acid (d, J= 16.8 Hz, 1H), 6.40 (s, 1H), methoxyphenyl) ac .22 (s, 2H), 3.95 (s, 3H), 3.87 (s, rylamido)benzoic 3H); MS (ESI+)m/z 408.1 acid and 5- ; 97.4% purity, RT 2.95 (chloromethyl) -1 - min (Method 12) methyl-1H- pyrazole________ (/?)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid 1 0 G N a) l-(4-bromomethoxybenzyl)methylpiperazine I I L^nh ■OCT OXr To a solution of 4-bromomethoxy-benzaldehyde (500 mg, 2.3 mmol, 1.0 equiv.), 1- methylpiperazine (389 pL, 3.5 mmol, 1.5 equiv.) and acetic acid (40 pL, 0.699 mmol, 0.3 equiv.) in 1,2-dichloroethane (10 mL) was added sodium triacetoxyborohydride (741 mg, 3.5 mmol, 1.5 equiv.) portion-wise maintaining the temperature at 0°C. The e was stirred at 25°C for 3 hours and was then quenched with saturated aqueous sodium bicarbonate solution (20 mL).
Then the e was extracted with dichloromethane (20 mL x3) and the combined organic layer washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated to give the d product as yellow oil (560 mg, crude) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 5 7.23 (d, J = 8.0 Hz, 1H), 7.07 (dd, J = 8.0 Hz, J2 = 2.0 Hz 1H), 6.99 (d, J = 1.6 Hz, 1H), 3.81 (s, 3H), 3.50 (s, 2H), 2.60 - 2.35 (m, 8H), 2.29 (s, 3H). b) 3-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehydeoar I oxoI \ To a solution of l-(4-bromomethoxybenzyl)methylpiperazine (250 mg, 0.836 mmol, 1.0 ) in anhydrous tetrahydrofuran (10 mL) at -78°C under a nitrogen atmosphere was added n-bulyllilhium (2.5 M in hexane, 1.00 mL, 3.0 equiv.) via syringe drop-wise over a WO 44620 period of 10 minutes. The resulting solution was stirred at -78°C for 10 minutes and then N,N- dimethylformamide (644 pL, 8.4 mmol, 10.0 equiv.) was added at -78°C over 10 minutes. The mixture was then stirred at 25 °C for 1 hour. The reaction was quenched with saturated ammonium chloride aqueous solution (10 mL) and the resultant mixture was extracted with ethyl acetate (20 mL x3). The combined organic layer was washed with brine (20 mL), dried over sulfate sodium, filtered and concentrated to give the desired product as yellow oil (225 mg, crude) which was used without further cation; MS (ESI+) m/z 249.1 (M+H)+. c) (E)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid oxr°I 0 0 uI 0 HO N H H 0 OH 0 OH To a on of 2-[(2-carboxyacetyl)amino]benzoic acid (100 mg, 0.448 mmol, 1.0 ) and 3-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehyde (223 mg, 0.896 mmol, 2.0 equiv.) in toluene (5 mL) was added piperidine (44 pL, 0.448 mmol, 1.0 equiv.) and the reaction mixture stirred at 110°C for 16 hours. The mixture was trated in vacuo and the residue purified by preparative HPLC to give the desired product as a white solid (15 mg, 8%) as the trifluoroacetic acid salt; NMR (CD3OD, 400 MHz) 5 8.71 (d, /= 8.0 Hz, 1H), 8.14 (d, / = 6.4 Hz, 1H), 7.69 (d, /= 15.6 Hz, 1H), 7.61 (t, /= 7.2 Hz, 1H), 7.43 (d, /= 7.6 Hz, 1H), 7.34 (s, 1H), 7.29 (d, / = 8.0 Hz, 1H), 7.19 (t, / = 8.0 Hz, 1H), 6.84 (d, / = 16.0 Hz, 1H), 3.97 (s, 2H), 3.95 (s, 3H), 3.30 - 3.20 (m, 4H), 3.10 - 2.90 (m, 4H), 2.85 (s, 3H). MS (ESI+) m/z 410.2 (M+H)+; 96.5% purity, RT 1.89 min (Method 11).
Ex Structure Data Method 69 iH NMR (DMSO - d6, 400 MHz) 5 Prepared 11.23 (s, 1H), 8.59 (d, /= 8.0 Hz, according to the 'OH 1H), 8.03 (dd, / = 8.0 Hz, / = 2.0 method for 68 (£)(3-(3-mcthoxy Hz, 1H), 7.67 - 7.55 (m, 2H), 7.52 - starting from 4- (morpholinomethyl)phenyl)acryla 7.43 (m, 2H), 7.36 (d, J= 7.6 Hz, bromomethoxymido )benzoic acid trifluoroacetic 1H), 7.19 (t, / = 8.0 Hz, 1H), 6.93 dehyde and acid salt (d, /= 16.0 Hz, 1H), 4.22 (s, 2H), morpholine 3.96 (s, 3H), 3.81 (br. s, 4H), 3.11 (br. s, 4H). MS (ESI+) m/z 397.1 (M+H)+; 95.1% purity, RT 5.41 min (Method 4) (/?)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic add (70) WO 44620 O, o O OH a) 4-bromo(chloromethyl)-l-methoxybenzeneoa HO cica I I To the solution of (4-bromomethoxy-phenyl)methanol (2.9 g, 13.4 mmol, 1.0 equiv.) and A/.iV-dimethylformamidc (51 pL, 0.668 mmol, 0.05 equiv.) in dichloromethane (30 mL) was added l chloride (1.5 mL, 20 mmol, 1.5 ) drop-wise maintaining the temperature at 0°C. The reaction mixture was then stirred at 40°C for 2 hours, cooled to room temperature and concentrated in vacuo. The residue was diluted with dichloromethane (30 mL) and the resulting solution washed with saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over sulfate sodium, filtered and concentrated to give the desired t as a light yellow solid (1.2 g) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 5 7.49 (d, J = 2.4 Hz, 1H), 7.41 (dd, J = 8.8 Hz, J = 2.0 Hz, 1H), 6.78 (d, J = 8.8 Hz, 1H), 4.60 (s, 2H), 3.87 (s, 3H). b) 4-((5-bromomethoxybenzyl)oxy)-l-methylpiperidine c'COr Cl 1 'XT To a solution of l-methylpiperidinol (178 pL, 1.5 mmol, 1.2 equiv.) in tetrahydrofuran (5 mL) was added sodium hydride (76.4 mg, 1.9 mmol, 60% purity in mineral oil, 1.5 equiv.) at 0°C. The mixture was stirred at 25°C for 1 hour. 4-Bromo (chloromethyl)-l-methoxybenzene (300 mg, 1.3 mmol, 1.0 equiv.) was then added and the mixture stirred for 11 hours at 60°C. The reaction was quenched by saturated s ammonium chloride (10 mL) under stirring and ted with ethyl acetate (5 mL x 3). The combined organic layer was washed with brine (10 mL), dried over sulfate sodium, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, dichloromethane: methanol = 100: 1 to 10: 1) to give the desired product as light yellow oil (270 mg); NMR (CDCI3, 400 MHz) 5 7.53 (d, / = 3.2 Hz, 1H), 7.34 (dd, / = 7.6 Hz, / = 3.2 Hz, 1H), 6.71 (d, /= 13.6 Hz, 1H), 4.52 (s, 2H), 3.80 (s, 3H), 3.40 - 3.50 (m, 1H), 2.80 - 2.65 (m, 2H), 2.30 (s, 3H), 2.30 - 2.10 (m, 2H), 2.05 - 1.90 (m, 2H), 1.85 - 1.65 (m, 2H). c) 4-methoxy(((l-methylpiperidinyl)oxy)methyl)benzaldehyde Ol'Xf 'O I I The title compound was prepared according to the procedure bed for the synthesis of 3-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehyde starting from 4-((5- bromomethoxybenzyl)oxy)-l-methylpiperidine. MS (ESI+) m/z 264.1 (M+H)+. d) (E)(3-(4-methoxy(((l-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic Cl ■N^kA0. o o O XT' N HO H O O OH I O OH I The title compound was prepared as the oroacetic acid salt according to the procedure described for the synthesis of (£’)(3-(3-methoxy((4-methylpiperazin-lyl )methyl)phenyl)acrylamido)benzoic acid (68) starting from 2-[(2-carboxyacetyl)amino]benzoic acid and 4-methoxy(((l-methylpiperidinyl)oxy)methyl)benzaldehyde (11%); H NMR de, 400 MHz, performed at 80°C) 5 11.17 (br. s, 1H), 8.58 (d, /= 10.8 Hz, 1H), 8.02 (d, /= 8.4 Hz, 1H), 7.70 - 7.55 (m, 4H), 7.18 - 7.05 (m, 2H), 6.65 (d, 7 = 20.8 Hz, 1H), 4.57 (s, 2H), 3.88 (s, 3H), 3.75 (br.s , 1H, partially obscured by water signal), 3.25 - 3.10 (m, 4H, lly obscured by water signal), 2.80 (s, 3H), 2.10 - 1.80 (m, 4H); MS (ESI+) m/z 425.2 (M+H)+; 98% purity, RT 2.52 min (Method 11).
Ex Structure Data Method 71 o iH NMR (CD3OD, 400 MHz) 5 8.70 Prepared according % N (d, /= 8.0 Hz, 1H), 8.12 (d, /= 7.2 to the method for 0 Cr OH Hz, 1H), 7.68 - 7.55 (m, 4H), 7.16 70 starting from 4- (£)(3 -(4-methoxy-3 -((prop (t, J= 7.6 Hz, 1H), 7.03 (d, J= 7.6 bromo yn Hz, 1H), 6.61 (d, / = 16.0 Hz, 1H), omethyl)-1 - yloxy)methyl)phenyl)acrylamido) 4.64 (s, 2H), 4.26 (d, J= 2.0 Hz, methoxybenzene benzoic acid 2H), 3.89 (s, 3H), 2.91 (t, 7=2.0 and propyn-l-ol Hz, 1H); MS (ESI+) m/z 388.1 (M+Na)+; 99% purity, RT 2.13 min (Method 10) 72 I o iH NMR (DMSO-4, 400 Prepared according N MHz) 5 11.45 (br. s, 1H), 8.61 (d, J to the method for 0 OH = 8.4 Hz, 1H), 8.01 (d, J= 8.0 Hz, 70 starting from 4- (£T)(3-(3-methoxy((prop 1H), 7.64 - 7.56 (m, 2H), 7.39 (s, 1- yn 1H), 7.35 - 7.30 (m, 2H), 7.18 (t, / = (chloromethyl) yloxy)methyl)phenyl)acrylamido) 7.6 Hz, 1H), 6.94 (d, /= 15.6 Hz, methoxybenzene c acid 1H), 4.54 (s, 2H), 4.23 (d, J= 2.4 and propyn-l-ol Hz, 2H), 3.88 (s, 3H), 3.48 (t, J = 2.0 Hz, 1H); MS (ESI+) m/z 366.2 (M+H)+; 97.8% purity, RT 2.18 min (Method 10) (/?)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73) 'O' N 'O' 0^ OH a) 4-bromo-l-methoxy(methoxymethyl)benzeneci^a i i ] To a solution of 4-bromo(chloromethyl)-l-methoxy-benzene (600 mg, 2.6 mmol, 1.0 equiv.) in tetrahydrofuran (5 mL) was added sodium methoxide (165 mg, 3.1 mmol, 1.2 equiv.) and the resultant mixture stirred under reflux for 12 hours. The reaction mixture was concentrated under vacuum to give a residue which was diluted with ethyl acetate (10 mL) and washed with water (10 mL x 3). The combined organic layer was washed with brine (10 mL x 2), dried over sodium sulfate, filtered and concentrated to give the desired product as yellow oil (430 mg) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 8 7.49 (d, J = 2.0 Hz, 1H), 7.36 (dd, / = 8.8 Hz, / = 2.4 Hz, 1H), 6.74 (d, / = 7.6 Hz, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 3.44 (s, 3H). b) 4-methoxy(methoxymethyl)benzaldehyde OX "O' o I I The title material was prepared according to the procedure described for the synthesis of 4-methoxy((4-methylpiperazin-l-yl)methyl)benzaldehyde starting from 4-bromo-l- y(methoxymethyl)benzene. ^ NMR (CDCI3, 400 MHz) 8 9.91 (s, 1H), 7.92 (s, 1H), 7.84 (dd, / = 8.4 Hz, / = 2.0 Hz, 1H), 6.99 (d, / = 8.4 Hz, 1H), 4.53 (s, 2H), 3.94 (s, 3H), 3.47 (s, c) (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid 'O' N O O' OH OH I The title nd was prepared according to the ure described for the synthesis of (£’)(3-(3-methoxy((4-methylpiperazin-l-yl)methyl)phenyl)acrylamido)benzoic acid (68) starting from 2-[(2-carboxyacetyl)amino]benzoic acid and oxy (methoxymethyl)benzaldehyde (25 %); 'H NMR (CD3OD, 400 MHz) 5 8.69 (d, 7= 8.0 Hz, 1H), 8.11 (d, 7 = 7.2 Hz, 1H), 7.65 -7.54 (m, 4H), 7.15 (t, 7=7.6 Hz, 1H), 7.02 (d,7= 8.8 Hz, 1H), 6.60 (d, 7= 15.6 Hz, 1H), 4.50 (s, 2H), 3.88 (s, 3H), 3.43 (s, 3H); MS (ESI+) mJz 342.1 (M+H)+; 99.2% purity, RT 2.94 min (Method 11). (/?)(3-(4-methoxy((propyn- l-ylamino)methyl)phenyl)acrylamido)benzoic acid (74) a) N-(5-bromomethoxybenzyl)propyn-l-amine CerBr* ^^nh2 ^oaBr A mixture of 5-bromomethoxybenzaldehyde (1.00 g, 4.65 mmol, 1.00 equiv.) and propyn-l-amine (298 uL, 4.65 mmol, 1.00 equiv.) in 1,2-dichloroethane (15.00 mL) was stirred for 0.5 hours at 25°C. Sodium triacetoxyborohydride (1.48 g, 6.98 mmol, 1.50 equiv.) and acetic acid (28 mg, 0.46 mmol, 0.10 equiv.) were then added at 0°C and the ing reaction stirred for 11.5 hours at 25 °C. The reaction mixture was quenched with 1 N hydrochloric acid (10 mL) and the solvent was removed under reduced pressure. The residue was diluted with dichloromethane (30 mL) and washed with saturated sodium bicarbonate aqueous (10 mL), water (10 mL x3) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was ed by silica gel column chromatography leum ether: ethyl acetate 1:0 to 10:1) to afford the desired product as colourless oil (1.10 g, 58%); 1H NMR (CDC13, 400 MHz) 5 7.39 (d, 7 = 2.0 Hz, 1H), 7.36 (dd, 7 = 8.8 Hz, J= 2.4 Hz. 1H), 6.75 (d, / = 8.4 Hz, 1H), 3.84 (s, 2H), 3.82 (s, 3H), 3.43 (d, / = 2.4 Hz, 2H), 2.26 (1,7 =2.4 Hz, 1H). b) tert-butyl omethoxybenzyl(propyn-l-yl)carbamate To the mixture of A/-(5-bromomcthoxybenzyl)propyn-l -amine (0.500 g, 1.97 mmol, 1.00 equiv.), di-/er/-butyl dicarbonate (1.29 g, 5.91 mmol, 3.00 equiv.) and 4- (dimethylamino)pyridine (0.024 g, 0.19 mmol, 0.10 ) in methanol (10 mL) was added triethylamine (199.34 mg, 1.97 mmol, 1.00 equiv.) and the resulting reaction mixture was stirred for 6 hours at 25°C. The reaction mixture was concentrated under reduced pressure to give a residue which was ed by silica gel column chromatography (petroleum ether: ethyl e= 50:1 to 20:1) to afford the desired product as colourless oil (0.41 g) which was used without further purification; 1H NMR , 400 MHz) 5 7.34 (dd, 7 = 8.8 Hz, 7 = 2.4 Hz, 1H), 7.31 (d, 7 = 2.0 Hz, 1H), 6.73 (d, 7= 8.4 Hz, 1H), 4.60 - 4.45 (m, 2H), 4.20 - 3.90 (m, 2H), 3.82 (s, 3H), 2.30 - 2.15 (m, 1H), 1.70 - 1.40 (m, 9H). c) tert-butyl 5-formylmethoxybenzyl(propyn-l-yl)carbamate O O I I To a on of tert-butyl 5-bromomethoxybenzyl(propyn-l-yl)carbamate (0.300 g, 0.85 mmol, 1.00 equiv.) in tetrahydrofuran (5 mL) at -78°C under a nitrogen atmosphere was added n-BuLi (2.5 M, 0.68 mL, 2.00 equiv.) slowly and the reaction stirred for 10 minutes at -78°C. Dimethyl ide (619 mg, 8.47 mmol, 10.00 equiv.) was then added and the resulting solution stirred for 30 minutes at -78°C. The reaction mixture was warmed to 20°C, quenched by the addition of aqueous saturated ammonium chloride (5 mL) and ted with ethyl acetate (5 mL x3). The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure to give a residue which was purified by silica gel column chromatography (petroleum ether: ethyl acetate 20:1 to 5:1) to afford the desired product as yellow oil (0.150 g) which was used without further purification; MS (ESI+) m/z 326.0 (M+Na)+. d) (3-(3-(((tert-butoxycarbonyl)(propyn-l-yl)amino)methyl)methoxyphenyl)- mido)benzoic acid o o o O^N O^N O HOAAn N H H O OH O O^ OH I I To a solution of 2-[(2-carboxyacetyl)amino]benzoic acid (100 mg, 0.45 mmol, 1.00 equiv.) and tert-butyl 5-formylmethoxybenzyl(propyn-l-yl)carbamate (136 mg, 0.45 mmol, 1.00 equiv.) in chloroform (5 mL) was added piperidine (4 mg, 0.04 mmol, 0.10 equiv.) and the resulting mixture stirred at 60°C for 12 hours. The reaction was concentrated under reduced re to afford the desired product as light yellow oil, which was used in the next step without further purification (250 mg); MS (ESI+) m/z 487.1 (M+Na)+. e) (E)(3-(4-methoxy((propyn-l-ylamino)methyl)phenyl)acrylamido)benzoic acid O OH I To a on of (£,)(3-(3-(((/er/-butoxycarbonyl)(propyn-l-yl)amino)methyl) methoxyphenyl)-acrylamido)benzoic acid (250 mg, crude) in dioxane (5 mL) was added 4M hydrochloric acid in dioxane (3 mL) and the mixture stirred at 25°C for 3 hours. The e was concentrated under reduced pressure and the residue was washed with ol (5 mL x3) to afford the desired product as a yellow solid (56.2 mg, 24.6%) as the hydrochloride salt; ^ NMR (DMSO-de, 400 MHz) 5 12.77 (hr. s, 1H), 8.60 (d, /= 8.0 Hz, 1H), 8.00 (d, /= 6.8 Hz, 1H), 7.74 (s, 1H), 7.62 (d, / = 8.4 Hz, 1H), 7.54 (d, / = 15.2 Hz, 1H), 7.47 (t, / = 7.2 Hz, 1H), 7.10 - 7.05 (m, 2H), 6.62 (d, /= 15.6 Hz, 1H), 3.94 (s, 2H), 3.85 (s, 3H), 3.62 (s, 2H), 3.37 (s, 1H); MS (ESI+) m/z 365.3 (M+H)+; 94.4% purity; RT = 1.54 min (Method 10).
Ex Structure Data Method iH NMR (DMSO-d6, 400 I o Prepared according 75 N MHz) 5 11.37 (s, 1H), 9.47 (hr. s, to the method for OH 1H), 8.61 (d, /= 8.4 Hz, 1H), 8.02 74 starting from 4- (E)(3-(3-methoxy((propyn- (d, /= 6.4 Hz, 1H), 7.66 - 7.60 (m, bromomethoxy- 1- 2H), 7.49 - 7.45 (m, 2H), 7.37 (d, J benzaldehyde and ylamino)methyl)phenyl)acrylamid = 7.6 Hz, 1H), 7.18 (t, /= 7.6 Hz, propyn-1 -amine o)benzoic acid 1H), 7.02 (d, /= 15.6 Hz, 1H), 4.18 (s, 2H), 3.93 - 3.90 (m, 5H), 3.75 (t, /= 2.4 Hz, 1H); MS (ESI+) m/z 365.2 (M+H)+; 99.6% purity, RT 1.57 min (Method ________ (/?)-/V-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76) a) 6-formylmethoxy(propyn-l-yloxy)phenyl acetate Ao Ao o /O. A To a solution of (6-formylhydroxymethoxyphenyl)acetate (0.38 g, 1.81 mmol 1.0 equiv., J. Med. Chem. 2000, 43, 1550-1562) and 3-bromoprop-l-yne (1.26 g, 9.03 mmol, 5.0 equiv.) in acetone (10 mL) was added potassium carbonate (1.50 g, 10.8 mmol, 6.0 equiv.) and the mixture stirred at 20°C for 12 hours. The mixture was filtered and the filtrate trated in vacuo to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 10:1 to 5:1) to give the desired product as light yellow gum (0.2 g) which was used t r purification; NMR (CDC13,400 MHz) 5 9.96 (s, 1H), 7.61 (d, / = 8.0 Hz, 1H), 7.07 (d, J = 8.0 Hz, 1H), 4.85 (d, / = 2.4 Hz, 2H), 3.88 (s, 3H), 2.59 (t, / = 2.4 Hz, 1H), 2.43 (s, b) oxymethoxypropynoxy-benzaldehyde Ao OH To a solution of (6-formylmethoxypropynoxyphenyl) acetate (2.10 g, 8.46 mmol, 1.0 equiv.) in water (10 mL) and tetrahydrofuran (10 mL) was added lithium hydroxide (0.79 g, 16.9 mmol, 2.0 equiv.) and the reaction stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to remove the tetrahydrofuran and the aqueous mixture was extracted with ethyl acetate (10 mL x 2). The organic layer was concentrated under reduced re to give a residue, which was purified by silica gel chromatography (petroleum ether: ethyl acetate = 15:1 to 10:1) to give the desired product as a light yellow solid (1.50 g, 86%); ^ NMR (CDCI3,400 MHz) 5 11.22 (s, 1H), 9.78 (s, 1H), 7.31 (d,J= 8.8 Hz, 1H), 6.75 (d,/= 8.8 Hz, 1H), 4.86 (s, 2H), 3.93 (s, 3H), 2.58 (t, / = 2.4 Hz, 1H). c) 2-[2-(dimethylamino)ethoxy]methoxypropynoxybenzaldehyde OH \ To a solution of 2-hydroxymethoxypropynoxybenzaldehyde (0.33 g, 1.60 mmol, 1.0 equiv.) in itrile (8 mL) was added 2-chloro-/V,/V-dimethylethanamine (0.35 g, 2.40 mmol, 1.5 equiv.), sodium iodide (0.048 g, 320 umol, 0.2 ) and caesium carbonate (1.30 g, 4.00 mmol, 2.5 equiv.) and the on stirred at 90°C for 3 hours. The mixture was then cooled to 20°C, diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel tography (petroleum ether: ethyl acetate 5:1 to 1:1) to give the desired product as light yellow gum (0.3 g, 68%); NMR (CDC13,400 MHz) 5 10.33 (s, 1H), 7.62 (d, /= 8.8 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.83 (d, J = 2.0 Hz, 2H), 4.29 (t, J = 5.6 Hz, 2H), 3.91 (s, 3H), 2.71 (t, J = 5.6 Hz, 2H), 2.57 (t, / = 2.4 Hz, 1H), 2.32 (s, 6H). d) (E)[2-[2-(dimethylamino)ethoxy]methoxypropynoxy-phenyl]propenoic I I /O. /O' 'OH To a solution of 2-[2-(dimethylamino)ethoxy]methoxyprop ynoxybenzaldehyde (0.22 g, 0.793 mmol, 1.0 equiv.) and malonic acid (0.165 g, 1.59 mmol, 2.0 equiv.) in pyridine (5 mL) was added piperidine (10.1 mg, 0.119 mmol, 0.15 equiv.) and the reaction stirred at 100°C for 1 hour. The e was cooled and trated under reduced pressure. The residue was diluted with water (5 mL) and the pH adjusted to 9 by the addition of saturated sodium carbonate solution. The aqueous mixture was extracted with ethyl acetate (5 mL x4), filtered and concentrated to give a crude product as a light yellow solid (0.25 g) as the sodium salt which was used t further purification; ^ NMR (DMSO-Je, 400 MHz) 8 7.74 (d, / = 16.0 Hz, 1H), 7.53 (d, / = 9.2 Hz, 1H), 6.97 (d, / = 9.2 Hz, 1H), 6.47 (d, / = 16.4 Hz, 1H), 4.92 (d, / = 2.0 Hz, 2H), 4.20 (t, /= 5.2 Hz, 2H), 3.80 (s, 3H), 3.66 (t, / = 2.4 Hz, 1H), 3.19 - 3.17 (m, 2H), 2.65 (s, 6H). e) (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxy- phenyl]propenamide I I \ \ .0. .0.
'OH LXXCN To a solution of (T)[ 2-[2-(di methyl ami no)cthoxy]mcthoxypropynoxy- phenyl]propenoic acid (0.1 g, 0.313 mmol, 1.0 ) and 3-aminobenzonitrile (0.037 g, 0.313 mmol, 1.0 equiv.) in pyridine (2 mL) was added phosphoryl chloride (29.10 pL, 0.313 mmol, 1.0 equiv.) at 0°C and the mixture was stirred at 0°C for 15 minutes. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford the desired nd as a light yellow solid (12 mg, 9%); 1H NMR (DMSO-Je, 400 MHz) 8 10.49 (s, 1H), 8.23 (s, 1H), 7.88-7.83 (m, 2H), 7.56-7.52 (m, 2H), 7.38 (d, J = 8.8 Hz, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.73 (d, / = 16.0 Hz, 1H), 4.91 (d, / = 2.4 Hz, 2H), 4.06 (t, / = 5.8 Hz, 2H), 3.78 (s, 3H), 3.65 (t, / = 2.2 Hz, 1H), 2.63 (t, / = 5.8 Hz, 2H), 2.22 (s, 6H); MS (ESI+) m/z 420.2 (M+H)+; 99.1% , RT 2.79 min d 8).
Ex Structure Data Method 77 I iH NMR (DMSO-d6,400 MHz) 5 Prepared according .29 (s, 1H), 7.88 - 7.82 (m, 2H), to the method for 0 1^ .0. 7.75 - 7.72 (m, 2H), 7.41 (d, J= 8.4 76 final step Hz, 1H), 7.38 - 7.33 (m, 1H), 6.99 starting from (£) (d, /= 8.8 Hz, 1H), 6.88 (d, /= 15.6 [2-[2- ((£’)-/V-(2-cyanophcnyl)(2-(2- Hz, 1H), 4.91 (d, /= 2.4 Hz, 2H), (dimethylamino)- (dimethylamino)ethoxy) -3 - 4.06 .8Hz, 2H), 3.78 (s, ethoxy ] -3 -methoxymethoxy (propyn-l - 3H), 3.65 (t, J= 2.4 Hz, 1H), 2.63 4-propynoxyyloxy )phenyl)acrylamide (t, J= 5.8 Hz, 2H), 2.22 (s, 6H); MS phenyl]prop (ESI+) m/z 420.2 (M+H)+; 99% enoic acid and 2- purity, RT 2.66 min (Method 8) aminobenzonitrile (/?)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy l)acrylamido)-benzoic acid (78) I I \ o o \ o o o /O. H .0.
O N OH H A mixture of 2-[2-(dimethylamino)ethoxy]methoxypropynoxybenzaldehyde (0.125 g, 0.45 mmol, 1.0 equiv.), 2-(2-carboxyacetamido)benzoic acid (0.111 g, 0.50 mmol, 1.1 equiv.) and piperidine (51 pL, 0.50 mmol, 1.1 equiv.) in anhydrous e was stirred under reflux for 4 hours. The reaction was then cooled to room temperature and the solvent removed in vacuo. The e was purified by preparative HPLC to provide the title compound (14 mg, 7 %); ‘H NMR (400 MHz, DMSO) 5 14.33 (s, 1H), 8.63 - 8.60 (m, 1H), 8.10 (dd, / = 7.8 Hz, J = 1.8 Hz, 1H), 7.96 (d, / = 17.4 Hz, 1H), 7.66 (d, 7=8.8 Hz, 1H), 7.44 - 7.39 (m, 1H), 7.09- 7.03 (m, 2H), 6.59 (d, /= 16.5 Hz, 1H), 4.98 (d, /= 2.3 Hz, 2H), 4.39 (t, /= 4.5 Hz, 2H), 3.86 (s, 3H), 3.68 (t, J=2.4 Hz, 1H), 3.65 - 3.59 (m, 2H), 2.98 (s, 6H); MS (ESI+) m/z 439.7 (M+H)+; 98% purity, RT 2.66 min (Method 2).
(/?)-/V-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79) "A0 o a) utyl(6-formylmethoxypropynoxy-phenoxy)azetidine-l-carboxylate Boc^NA0 /O. O .o.
To a solution of 2-hydroxymethoxypropynoxybenzaldehyde (0.160 g, 0.77 mmol, 1.0 equiv.) in A^AAlimethylformamidc (3 mL) was added potassium carbonate (0.322 g, 2.33 mmol, 3.0 equiv.) and / O H 'N CN H #^o #^0 CN The title compound was prepared according to the ure described for the sis of (£’)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (78) starting from /er/-butyl(6-formylmethoxy propynoxy-phenoxy)azetidine-l-carboxylate and yanoanilino)oxo-propanoic acid (42 %); MS (ESI+) m/z 526.2 (M+Na)+. c) (E)[2-(azetidinyloxy)methoxypropynoxyphenyl]-N-(2-cyanophenyl)prop enamide Boc'n^0 HN^0 O O o /O.
N N H H CN ^o CN To a solution of /er/-butyl[6-[(£,)(2-cyanoanilino)oxo-prop-l-enyl] methoxypropynoxy-phenoxy]azetidine-l-carboxylate (0.190 g, 0.37 mmol, 1.0 equiv.) in dichloromethane (6 mL) was added zinc bromide (0.850 g, 3.77 mmol, 10.0 equiv.) and the reaction mixture stirred at 25 °C for 4 hours. The mixture was concentrated and the residue added into saturated aqueous sodium onate solution (15 mL). The aqueous mixture was extracted with ethyl acetate (10 mL x3) and the combined organic phase was concentrated in vacuo to give the title compound as yellow oil (100 mg) which was used without further purification; MS (ESI+) m/z 403.9 (M+H)+. d) (E)-N-(2-cyanophenyl)[3-methoxy(l-methylazetidinyl)oxypropynoxy- phenyl]propenamide O O .0. .0.
N N CN H To a solution of (£,)[2-(azetidinyloxy)methoxypropynoxyphenyl]-/V-(2- cyanophenyl)propenamide (100 mg, 0.24 mmol, 1.00 ) in methanol (5 mL) was added sodium bicarbonate (42 mg, 0.49 mmol, 2.00 ) and aqueous formaldehyde (40 mg, 0.49 mmol, 37%, 2.00 equiv.) and the resulting mixture stirred at 25°C for 0.3 hours. Sodium cyanoborohydride (31 mg, 0.49 mmol, 2.00 equiv.) was added and stirring continued at 25°C for 1 hour. The mixture was ed and the filtrate concentrated under vacuum to afford a residue which was purified by preparative HPLC to provide the desired t as a white solid (12.0 mg, 11%); ^NMR (CD3OD,400 MHz) 5 7.93 (d,/= 15.6 Hz, 1H), 7.81 (d, 7=8.4 Hz, 1H), 7.74 (d, / = 8.0 Hz, 1H), 7.70 (t, / = 8.0 Hz, 1H), 7.40 (d, / = 9.2 Hz, 1H), 7.37 (t, / = 7.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 6.82 (d, J = 16.0 Hz, 1H), 4.72 - 4.68 (m, 1H), 3.82 (s, 3H), 3.80 - 3.76 (m, 2H), 3.42 - 3.34 (m, 2H), 3.01 (t, / = 2.4 Hz, 1H), 2.43 (s, 3H), propargyl CH2masked by residual water signal; LCMS: m/z 418.1 [M+H]+; 95.1% purity; RT = 2.55 min (Method 12). 2-[[(/?)(3-methoxypropynoxypyrrolidinyloxyphenyl)prop enoyl]amino]benzoic acid (80) HN—.a0 a) tert-butyl 3-(6-formylmethoxypropynoxyphenoxy)pyrrolidine-l-carboxylate •O. 0 The title compound was prepared according to the procedure described for the synthesis of /er/-butyl(6-formylmethoxypropynoxyphenoxy)azetidine- 1-carboxylate starting from 2-hydroxymethoxypropynoxybenzaldehyde and / 'OH ON To a solution of (T)[ 2-[2-(di methyl ami no)cthoxy]mcthoxyphcnyl]propcnoic acid (0.52 g, 0.471 mmol, 1.0 equiv.) in dichloromethane (5 mL) was added ropylethylamine (0.183 g, 1.41 mmol, 3.0 equiv.) and HATU (0.215 g, 0.565 mmol, 1.2 equiv.). The on was stirred at 20°C for 30 minutes, 3-aminobenzonitrile (0.084 g, 0.707 mmol, 1.5 eqwz'v.) was added and the resulting mixture stirred for 2 hours at 20°C. The reaction was washed with water (5mL x 3) and the organic phase was dried over ous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to afford the desired compound as a light yellow solid (40 mg, 23%); ^ NMR (DMSO-Je, 400 MHz) 5 10.53 (s, 1H), 8.23 (s, 1H), 7.96 (d, 7 = 16.0 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.56 - 7.53 (m, 2H), 7.22 - 7.20 (m, 1H), 7.14-7.11 (m, 2H), 6.80 (d, /= 15.6 Hz, 1H), 4.01 (t, /= 5.6 Hz, 2H), 3.83 (s, 3H), 2.60 (t, /= 6.0 Hz, 2H), 2.21 (s, 6H); MS (ESI+) m/z 366.2 (M+H)+; 100% purity, RT 2.71 min (Method 8).
Ex Stmcture Data Method I iH NMR (DMSO-cfg, 400 MHz) 5 Prepared according 92 \ 10.32 (s, 1H), 7.97 (d, J= 16.0 Hz, to the method for 0 o 1H), 7.84 (d, /= 8.0 Hz, 1H), 7.74 - 91 step c starting N 7.70 (m, 2H), 7.38 - 7.33 (m, 1H), from (£T)[2-[2- CN 7.25 - 7.23 (m, 1H), 7.16 - 7.12 (m, (dimethylamino)eth (£0-A^-(2-cyanophenyl)(2-(2- 2H), 6.94 (d, /= 16.0 Hz, 1H), 4.01 oxy]methoxy- (dimethylamino)ethoxy) (t, 7=5.6 Hz, 2H), 3.83 (s, 3H), phenyl]prop methoxyphenyl) mide 2.59 (t, 7= 6.0 Hz, 2H), 2.20 (s, enoic acid and 2- 6H); MS (ESI+) m/z 366.1 (M+H)+; aminobenzonitrile 98.9% purity, RT 2.29 min (Method (/?)-/V-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide a) 2-[2-(dimethylamino)ethoxy]methoxybenzaldehyde OH \ The title compound was prepared according to the procedure described for the synthesis of dimethylamino)ethoxy]methoxypropynoxybenzaldehyde starting from 2-hydroxymethoxybenzaldehyde and 2-ch 1 oro-iV,iV-dimcthy 1 cthanaminc (27% ; 'H NMR (CDCI3,400 MHz) 5 10.33 (s, 1H), 7.83 (d, 7 = 8.4 Hz, 1H), 6.56 (d, 7 = 8.8 Hz, 1H), 6.46 (s, 1H), 4.17 (t, 7 = 5.8 Hz, 2H), 3.88 (s, 3H), 2.82 (t, 7= 5.6 Hz, 2H), 2.38 (s, 6H); MS (ESI+) m/z 224.0 (M+H)+. b) (E)[2-[2-(dimethylamino)ethoxy]methoxyphenyl]propenoic acid I I \ \ x) "OH "O' •O' The title compound was ed according to the procedure described for the synthesis of (£’)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl]prop enoic acid starting from 2-(2-(dimethylamino)ethoxy)methoxybenzaldehyde and malonic acid (83% yield); ^ NMR (CD3OD,400 MHz) 5 8.01 (d, / = 21.6 Hz, 1H), 7.63 (d, /= 11.2 Hz, 1H), 6.68 - 6.45 (m, 2H), 6.38 (d, 7=21.2 Hz, 1H), 4.47 (t, 7=6.4 Hz, 2H), 3.86 (s, 3H), 3.71 (t,7 = 6.6 Hz, 2H), 3.04 (s, 6H); MS (ESI+) m/z 266.3 (M+H)+. c) (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide I I \ \ 'OH ^1 iHxXCN \ H O o The title compound was prepared as the trifluoroacetic acid salt according to the ure described for the synthesis of (T)-A/-(3-cyanophcnyl)[2-[2- (dimethylamino)ethoxy]methoxypropynoxy-phenyl]propenamide (76) starting from (£’)[2-[2-(dimethylamino)-ethoxy]methoxyphenyl]propenoic acid and 3- aminobenzonitrile (26% yield); NMR (CDC13,400 MHz) 5 8.31 (s, 1H), 8.04 (s, 1H), 7.92 - 7.88 (m, 2H), 7.45 - 7.36 (m, 3H), 6.76 (d, 7= 15.6 Hz, 1H), 6.53 (d, 7= 6.0 Hz, 1H), 6.48 (d, 7 = 2.0 Hz, 1H), 4.15 (t, 7 = 5.6 Hz, 2H), 3.85 (s, 3H), 2.85 (t, 7= 5.6 Hz, 2H), 2.40 (s, 6H); MS (ESI+) m/z 366 (M+H)+; 95.3% purity, RT 2.06 min (Method 5).
Ex Structure Data Method 94 I iH NMR (CD3OD, 400 MHz) 5 8.11 ed according \ (d, 7 = 16.0 Hz, 1H), 7.78 - 7.75 (d, to the method for o 0 7= 8.0 Hz, 2H), 7.72 - 7.68 (m, 93 step c starting H 2H), 7.38 (t, 7= 8.0 Hz, 1H), 6.76 - from (£T)[2-[2- 'O' 6.68 (m, 3H), 4.45 (t, 7= 4.6 Hz, (dimethylamino)eth (E) -/V-(2-cy anophenyl) -3 - [2- [2- 2H), 3.88 (s, 3H), 3.71 (t, 7=4.6 oxy] methoxy- (dimethylamino)ethoxy] Hz, 2H), 3.05 (s, 6H); MS (ESI+) phenyl]prop y-phenyl]propenamide m/z 366.1 (M+H)+; 94% purity, RT enoic acid and 2- trifluoroacetic acid salt 2.91 min d 11) aminobenzonitrile (/?)(3-(3,4-dimethoxy(propyn- l-yloxy)phenyl)acrylamido)benzoic acid (95) ■0 o O OH a) 3,4-dimethoxy(propyn-l-yloxy)benzaldehyde .0. '0 To a solution of 2-hydroxy-3,4-dimethoxybenzaldehyde (0.200 g, 1.09 mmol, 1 equiv., Inorganic Chemistry, 2004, 43, 4743-4750) in acetone (1.7 mL) was added ium carbonate (0.300 g, 2.17 mmol, 2 equiv.) and propargyl bromide (0.19 mL, 1.28 mmol, 1.2 mmol, 80 wt % in toluene) and the resulting suspension stirred at 60 °C overnight. The on was cooled to room temperature and the solid d by filtration and washed with acetone. The combined filtrate was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried over MgSCL and the solvent removed in vacuo. The e was purified by silica gel chromatography (petroleum ether: ethyl acetate 1:0 to 2:1) to afford the title compound as a white solid (0.133 g, 54 %); ^ NMR (400 MHz, CDCI3) 5 10.32 (s, 1H), 7.65 (d, 7=8.8 Hz, 1H), 6.81 (d, 7=8.8 Hz, 1H), 4.92 (d, 7 = 2.5 Hz, 2H), 3.94 (s, 3H), 3.90 (s, 3H), 2.49 (t, 7= 2.4 Hz, 1H). b) (E)(3-(3,4-dimethoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid "o "o o .0. H .0. ■o N OH H O o O^ OH The title compound was prepared according to the procedure described for the synthesis of (£,)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-l- yloxy)phenyl)acrylamido)benzoic acid (78) starting from 3,4-dimethoxy(propyn-lyloxy )benzaldehyde and 2-(2-carboxyacetamido)benzoic acid (16 % yield); ^ NMR (400 MHz, DMSO) 5 11.72 (s, 1H), 8.68 (d, 7 = 7.6 Hz, 1H), 8.06 (dd, 7= 8.0 Hz, 7= 1.6 Hz, 1H), 7.89 (d, 7= 16.0 Hz, 1H), 7.67 - 7.60 (m, 2H), 7.23 - 7.18 (m, 1H), 6.98 (d, 7= 8.8 Hz, 1H), 6.81 (d, 7 = 16.0 Hz, 1H), 4.88 (d, 7 = 2.5 Hz, 2H), 3.92 (s, 3H), 3.83 (s, 3H), 3.59 (t, 7 = 2.4 Hz, 1H); MS (ESI-) m/z 380.1 (M-H)-; 96.7% purity, RT 2.62 min (Method 3). (/?)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96) o o O OH a) 3,4-dimethoxy(pyridinylmethoxy)benzaldehyde .0. ‘O To a solution of 2-hydroxy-3,4-dimethoxybenzaldehyde (0.240 g, 1.32 mmol, 1 , Inorganic Chemistry, 2004, 43, 4743-4750) in acetonitrile (10.5 mL) was added potassium carbonate (0.546 g, 3.95 mmol, 3 equiv.), 3-picolyl chloride hydrochloride (0.216 g, 1.32 mmol) and sodium iodide (0.02 g, 0.13 mmol, 0.1 equiv.) and the resulting mixture stirred at 95 °C for 16 hours. The reaction was cooled to room temperature and poured into saturated potassium carbonate on. The acetonitrile was removed in vacuo and the aqueous phase extracted with ethyl acetate (x2). The combined c phase was washed with saturated potassium carbonate solution, dried over MgS04 and the solvent removed in vacuo. The e was purified by silica gel chromatography (petroleum ether: ethyl acetate 1:0 to 0:1) to afford the title compound as a white solid (0.182 g, 50%); ‘H NMR (400 MHz, CDC13) 5 10.14 (s, 1H), 8.67 (d,/= 1.8 Hz, 1H), 8.61 (dd, 7 = 4.8,/= 1.5 Hz, 1H), 7.82 - 7.77 (m, 1H), 7.60 (d,/= 8.8 Hz, 1H), 7.33 (dd, J = 7.8, 4.8 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 5.24 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H). b) (3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid [1 [1 0 0 "O "O 0 .0. H .0.
O N OH H 'O' ‘O' O^ OH ] The title compound was prepared according to the procedure described for the synthesis of (£,)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (78) starting from 3,4-dimethoxy(pyridin ylmethoxy)benzaldehyde and 2-(2-carboxyacetamido)benzoic acid (12 % yield); ^ NMR (400 MHz, DMSO) 5 11.78 (s, 1H), 8.71 (d,/= 1.8 Hz, 1H), 8.66 (d,/ = 7.6 Hz, 1H), 8.61 (dd,/ = 4.8 Hz, / = 1.5 Hz, 1H), 8.06 (dd, / = 7.8 Hz, 7 = 1.5, Hz, 1H), 7.99 - 7.94 (m, 1H), 7.78 (d, / = .8 Hz, 1H), 7.66 - 7.58 (m, 2H), 7.50 (dd, J = 7.7 Hz, J = 4.9, Hz, 1H), 123 - 1X1 (m, 1H), 6.98 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 15.7 Hz, 1H), 5.16 (s, 2H), 3.93 (s, 3H), 3.86 (s, 3H); MS (ESI+) m/z 435.3 (M+H)+; 98.6% purity, RT 2.91 min (Method 2).
(E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid r? H a) (E)(3-(4-bromomethoxyphenyl)acrylamido)benzoic acid XT0I o o o HO N H H O^TIH Br 0^ OH To a mixture of 2-[(2-carboxyacetyl)amino]benzoic acid (500 mg, 2.24 mmol, 1.0 equiv.) and 4-bromomethoxy-benzaldehyde (530 mg, 2.46 mmol, 1.1 equiv.) in toluene (5 mL) was added dine (19 mg, 0.224 mmol, 0.1 equiv.)- The mixture was stirred at 110°C for 10 hours. The precipitated solid was collected by filtration and suspended in IN hydrochloric acid (20 mL) and stirred at 20°C for 2 hours. The mixture was filtered and the collected solid dried under vacuum to afford the desired product as a yellow solid (400 mg, 47%). ^ NMR (400 MHz, DMSO-d6) 5 11.34 (s, 1H), 8.61 ((d, /= 8.0 Hz, 1H), 8.02 (dd, J 1.2 Hz, 7.6 Hz, 1H), 7.63 - 7.59 (m, 3H), 7.50 (s, 1H), 7.27 (d, / = 8.0 Hz, 1H), 7.19 (t, / = 8.0 Hz, 1H), 7.02 (d, / = 8.0 Hz, 1H), 3.93 (s, 3H). b) (E)(3-(3-methoxy(4-methylpiperazin-l-yl)phenyl)acrylamido)benzoic acid I o I o o o N N r?A H 0^ OH Br 0^ OH O A mixture of (£’)(3-(4-bromomethoxyphenyl)acrylamido)benzoic acid (100 mg, 0.266 mmol, 1.0 equiv.), 1-methylpiperazine (40 mg, 0.40 mmol, 1.5 equiv.), t-BuOK (90 mg, 0.799mmol, 3.0 equiv.) and os Pd G1 (18 mg, 0.027 mmol, 0.1 equiv.) in tetrahydrofuran (3 mL) was de-gassed and then heated to 80°C for 2 hours under a en atmosphere. The mixture was ed and concentrated to s under vacuum. The residue was purified by ative HPLC to afford the desired product as a yellow solid (16 mg, 12%) as the trifluoroacetic acid salt. ^ NMR (400 MHz, DMSO-d6) 5 11.36 (s, 1H), 8.62 ((d, /= 8.0 Hz, 1H), 8.02 (dd, / 1.2 Hz, 7.6 Hz, 1H), 7.62 - 7.56 (m, 2H), 7.38 (d, / = 1.2 Hz, 1H), 7.25 (d, / = 8.0 Hz, 1H), 7.18 (t, 7=8.4 Hz, 1H), 6.98 (d, 7=8.0 Hz, 1H), 6.83 (d, 7 =15.6 Hz, 1H), 3.89 (s, 3H), 2.87 (s, 3H) piperazine signals obscured under water signal; MS (ESI+) m/z 396.2 (M+H)+; 97.9% purity, RT 2.39 min (Method 11). (/?)(3-(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid o o. o. N N H H O OH Br' O OH A mixture of f)(4-bromomcthoxy-phcnyl)propcnoyl] ami no] benzoic acid (150 mg, 0.399 mmol, 1.0 equiv.), tert-butyX 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolanyl)-3,6- dihydro-2H-pyridine-l-carboxylate (1240 mg, 0.399 mmol, 1.0 equiv.), potassium carbonate (165 mg, 1.2 mmol, 3.0 ) and Pd(dppf)Cl2 (29 mg, 0.040 mmol, 1.0 equiv.) in N,N- dimethylformamide (1.5 mL) and water (0.3 mL) was sed and then heated to 100°C for 3 hours under a nitrogen atmosphere. After cooling to room temperature the mixture was diluted with dichloromethane: ol (10: 1), filtered through a silica pad and concentrated in vacuo.
The residue was then stirred at 25°C hydrochloric acid/methanol (2 mL, 8 mmol) for 30 minutes and concentrated under vacuum to give the desired product as a yellow solid (180 mg, 75%) as a hydrochloric acid salt. NMR (CD3OD, 400 MHz) 5 8.69 (d, 7 = 8.4 Hz, 1H), 8.14 (d, 7 = 6.4 Hz, 1H), 7.67 (d, 7= 15.6 Hz, 1H), 7.55 (t, 7 = 7.6 Hz, 1H), 7.27 (d, 7= 14.4 Hz, 3H), 7.17 (t, 7 = 7.2 Hz, 1H), 6.80 (d, 7 = 15.6 Hz, 1H), 5.91 (s, 1H), 3.92 (s, 3H), 3.90 - 3.81 (m, 2H), 3.44 (t, 7 = 6.0 Hz, 2H), 2.85 - 2.72 (m, 2H); MS (ESI+) m/z 379.1 (M+H)+; 100% purity, RT 1.54 min (Method 10). (/?)(3-(3-methoxy(l-methyl-l,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic add (99) I o I o o o N N H H CT OH OH HN. .N.
To a e of 2-[[(£,)[3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl]prop- 2-enoyl]amino]benzoic acid (180 mg, 0.476 mmol, 1.0 equiv.) (98) in methanol (3 mL) was added formaldehyde (1 mL, 37% aqueous). After stirring at 25°C for 30 minutes sodium triacetoxyborohydride (302 mg, 1.43 mmol, 3.0 equiv.) was added and the mixture stirred for 2 hours. The reaction was then concentrated in vacuo and the residue dissolved in dichloromethane: methanol (10:1) and filtered. The filtrate was concentrated in vacuo and the residue purified by preparative HPLC to give the desired t as a yellow solid (41 mg, 22%) as the trifluoroacetic acid salt; 'H NMR , 400 MHz) 5 8.72 (d, J = 8.4 Hz, 1H), 8.13 (dd, J= 8.0 Hz, 7= 1.6 Hz, 1H), 7.66 (d, /= 14.2 Hz, 1H), 7.62 (d, /= 7.2 Hz, 1H), 7.29 (d, /= 16.8 Hz, 3H), 7.21 (t, /= 6.8 Hz, 1H), 6.83 (d, /= 15.6 Hz, 1H), 5.90 (s, 1H), 4.11 - 4.04 (m, 1H), 3.93 (s, 3H), 3.84 - 3.66 (m, 2H), 3.39 - 3.33 (m, 1H), 3.02 (s, 3H), 2.89 - 2.83 (m, 2H); MS (ESI+) m/z 393.1 (M+H)+; 95.3 % purity, RT 1.61 min (Method 11). (/?)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100) I o I o 0 0 N N H H Br' OH OH A mixture of 2-[[(L)(4-bromomcthoxy-phcnyl)propcnoyl]amino]benzoic acid (150 mg, 0.399 mmol, 1.0 equiv.), ethylboronic acid (35.4 mg, 0.478 mmol, 1.2 ), cesium carbonate (390 mg, 1.20 mmol, 3.0 equiv.) and AdinBuP Biphenyl (26.7 mg, 0.04 mmol, 0.1 equiv.) in ylbutanol (1 mL) was de-gassed and then heated to 90°C for 2 hours under a nitrogen atmosphere. The cooled mixture was diluted with ethyl acetate (20 mL), washed with brine (2x5 mL) and the organic phase concentrated to dryness in vacuo and the residue purified by preparative HPLC to afford the d product as a yellow solid (43.0 mg, 32%); ^ NMR (CD3OD, 400 MHz) 5 8.72 (d, /= 8.0 Hz, 1H), 8.14 (dd, 7= 1.6 Hz, 7= 9.6 Hz, 1H), 7.68 (d, 7 = 16.0 Hz, 1H), 7.64 - 7.59 (m, 1H), 7.21 - 7.17 (m, 4H), 6.74 (d, 7= 15.6 Hz, 1H), 3.92 (s, 3H), 2.66 (q, 7 = 7.2 Hz, 2H), 1.20 (t, 7 = 7.6 Hz, 3H); MS (ESI-) m/z 324.1 (M-H)-. 97.9 % purity, RT 1.61 min (Method 8). (/?)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101) O Cr OH a) (E)(3-(3-bromomethoxyphenyl)acrylamido)benzoic acid ocr o o o HO N H H 0^ OH 0 O^ OH To a solution of 2-[(2-carboxyacetyl)amino]benzoic acid (500 mg, 2.24 mmol, 1.0 equiv.) in toluene (20 mL) was added 3-bromomethoxybenzaldehyde (506 mg, 2.35 mmol, 1.05 equiv.) and piperidine (95.4 mg, 1.12 mmol, 0.5 equiv.) and the resulting mixture stirred at 110 °C for 16 hours. The reaction was cooled to room temperature, IN hydrochloric acid (2 mL) was added and the mixture was ted with ethyl acetate (100 mL x2). The combined organic phase was concentrated under reduced pressure to afford the desired product as a white solid (300 mg, 36%) which was used without further purification; MS (ESI+) m/z 376.0 / 378.0 b) (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid 0 0 N N H H O O OH OH The title nd was ed as the trifluoroacetic acid salt according to the procedure described for the synthesis of (L)(3-(3-mcthoxy(4-mcthylpipcrazin-l - yl)phenyl)acrylamido)benzoic acid (97) starting from (L)(3-(3-hroino methoxyphenyl)acrylamido)benzoic acid and morpholine (14%); 'fi NMR (DMSO-de, 400 MHz) 5 11.24 (s, 1H), 8.60 (d, 7=8.4 Hz, 1H), 8.01 (d, 7 = 7.2 Hz, 1H), 7.65 - 7.50 (m, 2H), 7.35 (d, 7 =8.0 Hz, 1H), 7.27 (s, 1H), 7.18 (t,7 = 7.6 Hz, 1H), 7.01 (d, 7= 8.4 Hz, 1H), 6.75 (d, 7= 15.6 Hz, 1H), 3.84 (s, 3H), 3.78 - 3.67 (m, 4H), 3.05 - 2.94 (m, 4H); MS (ESI+) m/z 383.1 (M+H)+; 98.4% purity, RT 2.69 min d 11). 2-[[(/?)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102) O^ OH a) methyl 4-allylmethoxybenzoate o o .0. .0.
"O' o To a solution of methyl 4-bromomethoxybenzoate (28.00 g, 114.25 mmol, 1.00 equiv.) in A/.iV-dimethylformamidc (400 mL) was added allyl(tributyl)stannane (38.53 mL, 125.68 mmol, 1.10 equiv.) and Pd(PPli3)4 (13.20 g, 11.43 mmol, 0.10 equiv.). The e was degassed under vacuum and purged with nitrogen 3 times and the resulting mixture stirred at 80°C for 4 hours under a nitrogen atmosphere. Water (25 mL) and sodium fluoride (5 g) were added, the resultant mixture was d at 25°C for 30 minutes and then filtered. The filter cake was washed with ethyl acetate (20 mL x2). The combined filtrate was extracted with ethyl acetate (250 ml x3). The organic phase was combined and washed with brine (100 mL x2), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ethenethyl acetate 1000:1 to 800:1) to give the d product as colourless oil (21.2 g, 90%); NMR (DMSO, 400 MHz) 5 7.51 (dd, /= 8.0 Hz, / = 1.6 Hz, 1H), 7.45 (s, 1H), 7.21 (d, / = 7.6 Hz, 1H), 5.96 - 5.89 (m, 1H), 5.06 - 5.01 (m, 2H), 3.83 (s, 3H), 3.82 (s, 3H), 3.36 (s, 2H). b) methyl 4-(cyclopropylmethyl)methoxybenzoate o o .0. .0.
"O' "O' A solution of diethlyzinc in toluene (1 M, 155.16 mL, 4.00 equiv.) was added to dichloromethane (100 mL) under a nitrogen atmosphere. The solution was cooled in an ice bath, a solution of trifluoroacetic acid (12.35 mL, 166.80 mmol, 4.30 equiv.) in romethane (100 mL) was added drop-wise and the reaction mixture stirred for 20 minutes at 0°C. A solution of diiodomethane (12.52 mL, 155.16 mmol, 4.00 equiv.) in dichloromethane (100 mL) was added and the reaction stirred for 20 minutes. Methyl lmethoxybenzoate (8.00 g, 38.79 mmol, 1.00 ) was then added and the resulting mixture stirred for 48 hours at 20°C. The mixture was poured into water (300 mL) and ted with romethane (200 mL x3). The ed organic phase was washed with brine (200 mL), dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by preparative HPLC to provide the desired product as a yellow liquid (3.5 g, 41%); NMR (CDCI3, 400 MHz) 5 7.61 (dd, / = 7.6 Hz, / = 1.6 Hz, 1H), 7.51 (s, 1H), 7.36 (d, / = 7.6 Hz, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 2.58 (d,/= 6.8 Hz, 2H), 1.05 - 1.01 (m, 1H), 0.52 - 0.50 (m, 2H), 0.20 - 0.18 (m, 2H). c) [4-(cyclopropylmethyl)methoxy-phenyl]methanol /O. OH To a solution of methyl lopropylmethyl)methoxybenzoate (3.50 g, 15.89 mmol, 1.00 equiv.) in tetrahydrofuran (50 mL) was added DIBAL-H (1 M, 47.7 mL, 3.00 equiv.) at 0°C and the on was stirred at 25 °C for 1 hour. The e was quenched with water (100 mL) and acidified with 6 N hydrochloric acid until the pH was 6~7. The mixture was extracted with ethyl acetate (100 mL x3). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo to afford the desired product as a yellow liquid (3.4 g) which was used without further purification; 1H NMR (CDCI3, 400 MHz) 5 7.29 (d, J = 8.0 Hz, 1H), 6.92 - 6.90 (m, 2H), 4.69 (s, 2H), 3.88 (s, 3H), 2.55 (d, J = 6.8 Hz, 2H), 1.06 -1.02 (m, 1H), 0.51 - 0.48 (m, 2H), 0.21 - 0.18 (m, 2H). d) 4-(cyclopropylmethyl)methoxy-benzaldehyde To a solution of [4-(cyclopropylmethyl)methoxyphenyl]methanol (3.40 g, 17.69 mmol, 1.00 equiv.) in dichloromethane (30 mL) was added artin periodinane (26.26 g, 61.92 mmol, 19.17 mL, 3.50 equiv.) at 0°C and the reaction was stirred at 25°C for 1 hour. The reaction was ed with saturated aqueous sodium sulphite (80 mL) and saturated aqueous sodium carbonate (50 mL) at 0°C and the resulting mixture extracted with ethyl acetate (100 mL x4). The combined organic phase was washed with brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography leum ethenethyl acetate 20:1) to provide the desired product as a colourless liquid (2.6 g, 77%); NMR (CDCR, 400 MHz) 5 9.95 (s, 1H), 7.48 (d, /= 7.6 Hz, 1H), 7.43 (d, / = 7.6 Hz, 1H), 7.37 (s, 1H), 3.90 (s, 3H), 2.61 (d, / = 6.8 Hz, 2H), 1.09 - 1.04 (m, 1H), 0.56 - 0.51 (m, 2H), 0.21 - 0.20 (m, 2H). e) 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid 0 0 0 HO N H H OH OH To a solution of 4-(cyclopropylmethyl)methoxybenzaldehyde (2.30 g, 12.09 mmol, 1.00 equiv.) in toluene (50 mL) was added 2-[(2-carboxyacetyl)amino]benzoic acid (2.97 g, 13.30 mmol, 1.10 equiv.) and piperidine (120 pL, 1.21 mmol, 0.10 equiv.) and the mixture stirred at 130°C for 6 hours. The mixture was concentrated in vacuo and the e purified by preparative HPLC to provide the title compound as a white solid (2.0 g, 47%); ^ NMR (CD3OD, 400 MHz) 5 8.72 (d, /= 8.4 Hz, 1H), 8.13 (dd, /= 8.0 Hz, 7= 1.6 Hz, 1H), 7.65 (d, / = .6 Hz, 1H), 7.59 (t, / = 6.8 Hz, 1H), 7.29 (d, / = 7.6 Hz, 1H), 7.20 - 7.15 (m, 3H), 6.75 (d, / = .6 Hz, 1H), 3.90 (s, 3H), 2.55 (d, / = 6.8 Hz, 2H), 1.05 -1.01 (m, 1H), 0.50 - 0.47 (m, 2H), 0.19-0.18 (m, 2H); MS (ESI+) m/z 352.1 [M+H]+; 100% , RT 2.90 min (Method 9).
Ex Structure Data Method 103 1 I 0 H NMR (DMSO-d6, 400 MHz) Prepared according N 511.29 (s, 1H), 8.62 (d, /= 8.4 Hz, to the method for 0 OH 1H), 8.01 (dd, / = 1.2 Hz, 9.2 Hz, 97 starting from 4- 0^r? 1H), 7.62 - 7.55 (m, 2H), 7.34 (s, bromo-3 -methoxy- (£)(3-(3-mcthoxy 1H), 7.24 (d, /= 8.4 Hz, 1H), 7.18 benzaldehyde, 2- morpholinophenyl)acrylamido)b (t, J= 4.0 Hz, 1H), 6.90 (d, J= 8.4 1(2- enzoic acid oroacetic acid Hz, 1H), 6.79 (d, /= 15.6 Hz, 1H), carboxyacetyl)amin salt 3.88 (s, 3H), 3.75 - 3.72 (m, 4H), o] benzoic acid and 3.05 - 3.03 (m 4H); MS (ESI+) m/z morpholine 383.1 ; 99.5% purity, RT 2.76 min (Method 11) 104 1H NMR (CD3OD, 400 MHz) 5 8.71 N O Prepared according N (d, /= 8.4 Hz, 1H), 8.14 (dd, /= 1.2 to the method for 'O' OH Hz, 7.6 Hz, 1H), 7.68 - 7.64 (m, 98 and then 99 (£)(3-(4-mcthoxy( 1 - 2H), 7.62 (t, J= 2.4 Hz, 1H), 7.51 starting from {E) methyl-1,2,3,6- (d, /= 2.4 Hz, 1H), 7.19 (t, J= 7.6 (3-(3-bromo tetrahydropyridin Hz, 1H), 7.10 (d, /= 8.8 Hz, 1H), methoxyphenyl)acr yl)phenyl) acrylamido)benzoic 6.66 (d, J= 15.6 Hz, 1H), 5.88 (s, ylamido)benzoic acid trifluoroacetic acid salt 1H), 4.11 - 3.41 (m, 6H), 3.10 - 2.76 acid (m, 6H); MS (ESI+) m/z 393.2 (M+H)+; 99.0% purity, RT 2.48 min (Method 11) 105 o 1H NMR (DMSO-dg, 400 MHz) 5 ed according N 11.30 (s, 1H), 8.62 (d, J= 7.6 Hz, to the method for 0 0^ OH 1H), 8.01 (dd, / = 1.6 Hz, 8.0 Hz, 100 starting from I 1H), 7.64 - 7.45 (m, 4H), 7.17 (t, J = (E)(3-(3-bromo- (3-(3-ethyl 8.0 Hz, 1H), 7.01 (d, J = 8.4 Hz, 4- methoxyphenyl)acrylamido)benz 1H), 6.73 (d, /= 15.6 Hz, 1H), 3.84 methoxyphenyl)acr oic acid (s, 3H), 2.60 (q, J= 7.6 Hz, 2H), ylamido)benzoic 1.16 (t, J= 7.6 Hz, 3H); MS (ESI+) acid m/z 348.1 +; 95.9% purity, RT 3.16 min (Method 11) 106 iH NMR (CDC13, 400 MHz) 511.18 0 Prepared according N (s, 1H), 8.92 (d, /= 8.8 Hz, 1H), to the method for 'O' 0 OH 8.15 (dd, J= 1.6 Hz, 9.6 Hz, 1H), 102 starting from (£)(3-(3- 7.74 (d, J= 15.6 Hz, 1H), 7.67 - methyl 3-bromo (cyclopropylmethyl) 7.62 (m, 1H), 7.54 (d, J= 4.0 Hz, methoxybenzoate methoxyphenyl)acrylamido)benz 1H), 7.44 (dd, J = 2.4 Hz, 10.8 Hz, oic acid 1H), 7.15 - 7.12 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 6.49 (d, J= 15.2 Hz, 1H), 3.87 (s, 3H), 2.55 (d, J= 6.8 Hz, 2H), 1.08 - 1.05 (m, 1H), 0.55 - 0.52 (m, 2H), 0.24 - 0.20 (m, 2H); MS (ESI+) m/z 352.0 (M+H)+; 96.9% , RT 2.97 min (Method 2-[[(£T)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid (107) I 0 'O' OH a) ethyl 2-(4-formylnitrophenoxy)acetate rxr* o2n To a solution of 4-hydroxynitrobenzaldehyde (40.00 g, 239.35 mmol, 1.00 equiv.) in acetonitrile (100 mL) was added ethyl 2-chloroacetate (44.00 g, 359.03 mmol, 38.26 mL, 1.50 equiv.), sodium iodide (17.94 g, 119.68 mmol, 0.50 equiv.) and potassium carbonate (99.24 g, 718.05 mmol, 3.00 equiv.) and the resultant mixture stirred at 80°C for 4 hours. The reaction e was cooled to 25 °C and filtered. The solid was washed with ethyl acetate (100 mL) and the combined filtrate was washed with brine (50 mL x2). The combined organic layers were dried over sodium e, concentrated under reduced pressure and the e purified by silica gel column chromatography (petroleum ethenethyl acetate 10:1 to 3:1) to give the desired product as a yellow solid (15.50 g, 26%); NMR d6, 400 MHz) 5 9.95 (s, 1H), 8.44 (d, 7=2.0 Hz, 1H), 8.16 (dd, 7=8.8 Hz, 7 = 2.4 Hz, 1H), 7.51 (d, 7= 8.8 Hz, 1H), 5.17 (s, 2H), 4.19 (q, 7= 6.8 Hz, 2H), 1.21 (t, 7= 6.8 Hz, 3H). b) 3-oxo-4H-l,4-benzoxazinecarbaldehyde o2nxr° r °XHJT° To a solution of ethyl 2-(4-formylnitrophenoxy)acetate (9.30 g, 36.73 mmol, 1.00 equiv.) in acetic acid (20.00 mL) was added iron powder (12.31 g, 220.37 mmol, 6.00 equiv.) and the mixture stirred at 60°C for 16 hours. The reaction mixture was diluted with dichloromethane (50 mL) and methanol (50 mL), stirred at 25 °C for 1 hour and then ed. The filtrate was concentrated in vacuo to give the desired product as a yellow solid which was used without further purification (4.40 g, 67%); NMR (DMSO-d6, 400 MHz) 5 10.99 (hr. s, 1H), 9.84 (s, 1H), 7.54 (dd, J= 8.0 Hz, J= 1.6 Hz, 1H), 7.38 (d,J= 1.2 Hz, 1H), 7.15 (d,J= 8.4 Hz, 1H), 4.72 (s, 2H). c) 4-methyloxo-l,4-benzoxazinecarbaldehyde To a mixture of 3-oxo-47/-l,4-benzoxazinecarbaldehyde (3.27 g, 18.46 mmol, 1.00 equiv.) and caesium carbonate (18.04 g, 55.38 mmol, 3.00 equiv.) in acetonitrile (20.00 mL) was added methyl iodide (2.30 mL, 36.92 mmol, 2.00 equiv.) and the mixture d at 80 °C for 2 hours. The reaction was cooled to 25 °C and d with ethyl acetate (30 mL). The resultant mixture was filtered and the filtrate trated under reduced pressure to give the d product which was used without further purification (3.50 g, 99%); ^ NMR (DMSO-Je, 400 MHz) 5 9.91 (s, 1H), 7.63-7.60 (m, 2H), 7.20 (d, /= 8.8 Hz, 1H), 4.79 (s, 2H), 3.34 (s, 3H). d) (4-methyl-2,3-dihydro-l,4-benzoxazinyl)methanol TlX0 —^ CO^HI I To a solution of 4-methyloxo-l,4-benzoxazinecarbaldehyde (5.90 g, 30.86 mmol, 1.00 equiv.) in tetrahydrofuran (100 mL) was added BHrMciS (10 M, 30.86 mL, 10.00 equiv.) drop-wise at 0°C and the resultant mixture stirred at 60°C for 2 hours. The reaction was quenched with methanol (100 mL) at 25 °C and concentrated in vacuo. The residue was dissolved in methanol (100 mL) and stirred at 60°C for 2 hr. The solvent was removed under reduce re to give the crude product, which used directly in the next step (7.0 g); MS (ESI+) m/z 180.1 (M+H)+. e) 4-methyl-2,3-dihydro-l,4-benzoxazinecarbaldehyde CO'0" (XT0I ] To a solution of hyl-2,3-dihydro-l,4-benzoxazinyl)methanol (7.00 g, 39.06 mmol, 1.00 equiv.) in dichloromethane (30.00 mL) was added Dess-Martin periodinane (24.85 g, 58.59 mmol, 18.14 mL, 1.50 equiv.) at 0 °C and the mixture stirred at 25 °C for 10 minutes. The reaction was quenched with saturated aqueous sodium lfate (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layer was washed with saturated sodium bicarbonate (30 mL x2) and brine (30 mL x 2), dried over sodium sulfate and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (petroleum ethenethyl acetate 1:0 to :1) to give the desired product as a yellow oil (2.30 g, 33%); MS (ESI+) m/z 178.0 (M+H)+. f) 2-[[(E)(4-methyl-2,3-dihydro-l,4-benzoxazinyl)propenoyl]amino]benzoic acid ccr°I 0 0 5 I 0 HOAA N OH "O' 0^ OH ] To a solution of 4-methyl-2,3-dihydro-l,4-benzoxazinecarbaldehyde (2.46 g, 13.88 mmol, 1.00 equiv.) and 2-[(2-carboxyacetyl)amino]benzoic acid (3.10 g, 13.88 mmol, 1.00 equiv.) in e (20 mL) was added piperidine (275 p,L, 2.78 mmol, 0.20 equiv.) and the mixture stirred at 110 °C for 16 hours. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC to provide the desired product as a yellow solid (3.26 g, 69%); ^ NMR d6, 400 MHz) 5 11.29 (s, 1H), 8.62 (d, /= 8.0 Hz, 1H), 8.00 (dd, / = 8.0 Hz,/= 1.6 Hz, 1H), 7.61 (t, 7=8.0 Hz, 1H), 7.53 (d,/= 15.2 Hz, 1H), 7.16 (t,/= 8.0 Hz, 1H), 7.06 (d, / = 2.0 Hz, 1H), 6.97 (d, / = 8.4 Hz, 1H), 6.72 - 6.68 (m, 2H), 4.27 (t, / = 4.4 Hz, 2H), 3.25 (t, /= 4.4 Hz, 2H), 2.90 (s, 3H). MS (ESI+) m/z 339.1 [M+H]+; 100% purity; RT = 1.27 min (Method 6). (/?)(3-(2-methyloxoisoindolinyl)acrylamido)benzoic acid (108) o o —N H a) 6-vinylisoindolin-l-one WO 44620 o o HN HN A mixture of 6-iodoisoindolin-l-one (1.00 g, 3.86 mmol, 1.0 equiv.), 4,4,5,5- tetramethylvinyl-l,3,2-dioxaborolane (0.892 g, 5.79 mmol, 1.5 equiv.), tetrakis(triphenylphosphine)palladium(0) (0.446 g, 0.386 mmol, 0.1 equiv.) and potassium carbonate (1.07 g, 7.72 mmol, 2.0 equiv.) in dioxane (15 mL) and water (3 mL) was degassed and purged with nitrogen 3 times and then d at 90°C for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated under reduced re to give a residue which was washed petroleum ether/ethyl acetate (10/1, 30 mL) and the solid collected by filtration to give the desired product as a yellow solid (0.6 g, 73%); MS (ESI+) m/z 160.3 (M+H)+. b) 2-methylvinylisoindolin-l-one o o HN —N To a suspension of 6-vinylisoindolin-l-one (0.160 g, 1.0 mmol, 1.00 equiv.) in acetonitrile (5 mL) was added caesium carbonate (0.823 g, 2.53 mmol, 2.5 equiv.) and methyl iodide (75 pL, 1.21 mmol, 1.20 equiv.) and the resultant mixture was stirred at 80°C for 1.5 hours. The mixture was cooled to 20°C, diluted with ethyl e (20 mL) and ed. The filtrate was washed with brine (10 mL) and the organic phase was concentrated under reduced pressure to afford the desired product (0.180 g) as light yellow gum which was used without further purification; MS (ESI+) m/z 174.1 (M+H)+. c) 2-methyloxoisoindolinecarbaldehyde o o —N —N To a solution of 2-methylvinylisoindolin-l-one (0.160 g, 0.92 mmol, 1.00 equiv.) in dioxane (10 mL) and water (1 mL) was added 4-methylmorpholine /V-oxide monohydrate (146 pL, 1.39 mmol, 1.50 equiv.) and osmium(IV) oxide (0.070 g, 0.28 mmol, 0.30 equiv.) and e was stirred at 20°C for 10 minutes. Sodium ate (0.800 g, 3.74 mmol, 4.05 equiv.) was added and the resultant mixture was stirred at 20°C for an additional 1.5 hours. The mixture was diluted with ethyl acetate (30 mL) and filtered. The filtrate was washed with brine (10 mL) and the c layer was concentrated under reduced pressure to afford the desired product (0.170 g) as light yellow gum which was used without further purification; MS (ESI+) m/z 176.1 (M+H)+. d) (E)(3-(2-methyloxoisoindolinyl)acrylamido)benzoic acid o o o o o O HO N —N H —N H O OH O OH To a mixture of 2-methyloxoisoindolinecarbaldehyde (0.080 g, 0.46 mmol, 1.00 equiv.) and 2-[(2-carboxyacetyl)amino]benzoic acid (0.102 g, 0.46 mmol, 1.00 equiv.) in toluene (3 mL) was added piperidine (7 pL, 0.07 mmol, 0.15 equiv.) and the mixture was stirred at 120°C for 2 hours. The reaction was concentrated under reduced pressure. The residue was triturated with methanol (5 mL) and IN hydrochloric acid (2 mL) and the solid collected by filtration to afford the desired product (0.021 g, 13% yield) as a grey solid; ^ NMR (DMSO-Je, 400 MHz) 5 11.40 (br. s., 1H), 8.60 (d, 7=8.4 Hz, 1H), 8.03 -7.94 (m, 2H), 7.93 (d,/= 1.6 Hz, 1H), 7.72 (d, / = 15.6 Hz, 1H), 7.65 - 7.62 (m, 2H), 7.03 - 7.02 (m, 1H), 7.10 (d, / = 15.6 Hz, 1H), 4.50 (s, 2H), 3.08 (s, 3H); MS (ESI+) m/z 337.1 ; 95.8% purity, RT 1.66 min (Method 6). -(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid (109) O' N CT OH a) (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic acid Xcr° Xcr° H i To a mixture of 3-oxo-4H-l,4-benzoxazinecarbaldehyde (0.600 g, 3.39 mmol, 1.00 equiv.) and caesium carbonate (3.31 g, 10.17 mmol, 3.00 equiv.) in A/.N-di methyl form amide (6 mL) was added methyl iodide (0.42 mL, 6.78 mmol, 2.00 ) and the mixture was stirred at 90°C for 1 hour. The reaction was cooled to 20°C, diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was dried over sodium sulfate, ed and concentrated under reduced pressure to give the title compound as a light yellow solid (0.600 g) which used without further purification; ^ NMR (CDCI3, 400 MHz) 8 9.90 (s, 1H), 7.60 (dd, J = 8.0 Hz, /= 1.6 Hz, 1H), 7.50 (d,/= 1.6 Hz, 1H), 7.12 (d,/= 8.0 Hz, 1H), 4.69 (s, 2H), 3.42 (s, b) (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][l,4]oxazinyl)acrylamido)benzoic x:CL° -ax 0 XL /5s. 0 0 I O' N OH OH I To a mixture of 4-methyloxo-l,4-benzoxazinecarbaldehyde (0.060 g, 0.31 mmol, 1.00 equiv.) and 2-[(2-carboxyacetyl)amino]benzoic acid (0.070 g, 0.31 mmol, 1.00 equiv.) in toluene (3 mL) was added piperidine (3 pL, 0.10 equiv.) and the resultant e stirred at 110°C for 12 hours. The reaction was cooled to 20°C and the resultant precipitate collected by tion, washed with methanol (3 mL) and dried under vacuum to give the desired product as a light yellow solid (0.056 g, 48%); 56 mg (48%);^ NMR (DMSO-X 400 MHz) 8 13.61 (hr. s., 1H), 11.36 (s, 1H), 8.61 (d, 7=8.0 Hz, 1H), 8.02-7.99 (m, 1H), 7.64 - 7.54 (m, 2H), 7.47 - 7.43 (m, 2H), 7.21 - 7.15 (m, 2H), 6.86 (d, /= 16.0 Hz, 1H), 4.70 (s, 2H), 3.30 (s, 3H); MS (ESI+) m/z 353.1 ; 95% purity, RT 1.76 min (Method 6).
Ex Structure Data Method 110 1H NMR (DMSO-d6, 400 MHz) 5 0 Prepared according N 11.30 (s, 1H), 8.61 (d, J = 8.0 Hz, to the method for N 0^ OH 1H), 8.00 - 7.98 (m, 1H), 7.61 - 7.57 108 (final step) I (m, 1H), 7.44 (d, J = 16.0 Hz, 1H), starting from 4- CE)(3-(4-methyl-3,4-dihydro- 7.16 - 7.12 (m, 2H), 7.08 - 7.07 (m, methyl-3,4- 2H-benzo[b] [ 1,4] oxazin-7 - 1H), 6.96 (d, J = 8.0 Hz, 1H), 6.55 o-2H- yl)acrylamido)benzoic acid (d, /= 16.0 Hz, 1H), 4.23 - 4.21 (m, benzofb] [1,4] oxazi 2H), 3.34 - 3.31 (m, 2H), 2.90 (s, necarbaldehyde 3H); MS (ESI+) m/z 339.1 (M+H)+; and 2-(2- 98.7% purity, RT 1.86 min (Method carboxyacetamido) 6) benzoic acid o iH NMR (DMSO-cfg, 400 MHz) 5 H ed according 111 N 13.60 (br. s„ 1H), 11.33 (s, 1H), to the method for "O' OH 10.80 (s, 1H), 8.58 (d, J = 8.0 Hz, 108 (final step) (£)(3-(3-oxo-3,4-dihydi'o-2H- 1H), 8.01 - 7.99 (m, 1H), 7.64 - 7.60 starting from 3- benzofb] [1,4] oxazin (m, 1H), 7.52 (d, J = 16.0 Hz, 1H), oxo-3,4-dihydroyl )acrylamido)benzoic acid 7.34 - 7.31 (m, 1H), 7.19 - 7.16 (m, 2H- 2H), 7.00 (d, J = 8.0 Hz, 1H), 6.63 benzofb] [1,4] oxazi (d, J = 16.0 Hz, 1H ), 4.64 (s, 2H); necarbaldehyde MS (ESI+) m/z 339.0 (M+H)+; and 2-(2- 95.2% purity, RT 1.67 min (Method carboxyacetamido) 6) benzoic acid o iH NMR (DMSO-dg, 400 MHz) 5 I Prepared according 112 N 11.37 (br. s„ 1H), 8.63 (d, J= 8.0 to the method for "O' OH Hz, 1H), 8.02 - 7.99 (m, 1H), 7.65 - 108 (final step) (E)(3 thyl-3 -oxo-3,4- 7.58 (m, 3H), 7.42 - 7.40 (m, 1H), starting from 4- dihydro-2H-benzo[b] [1,4]oxazin- 7.19 - 7.15 (m, 1H), 7.04 (d, J= 8.0 methyloxo-l,4- crylamido)benzoic acid Hz, 1H), 6.88 (d, / = 16.0 Hz, 1H), benzoxazine 4.71 (s, 2H), 3.35 (s, 3H); MS carbaldehyde and (ESI+) m/z 353.0 (M+H)+; 94% 2-(2- purity, RT 1.88 min (Method 6) carboxyacetamido) benzoic acid (/?)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)propen- 1-one (113) a) (3-ethyl(propyn-l-yloxy)phenyl)acrylic acid To a mixture of 3-ethylpropynoxybenzaldehyde (0.28 g, 1.49 mmol, 1.0 equiv.) and malonic acid (0.232 g, 2.23 mmol, 1.5 equiv.) in pyridine (5 mL) was added piperidine (0.013 g, 0.149 mmol, 0.1 equiv.) at 25°C and the resulting solution stirred at 120°C for 12 hours. The pH of the solution was ed to pH = 3 with IN hydrochloric acid and the resulting precipitate collected to afford the title compound as a yellow solid (0.32 g, 86%); lU NMR (CDC13, 400 MHz) 5 7.74 (d, / = 15.6 Hz, 1H), 7.39 (d, / = 7.2 Hz, 2H), 6.98 (d, /= 8.4 Hz, 1H), 6.34 (d, /= 16.0 Hz, 1H). 4.77 (d, /= 2.0 Hz, 2H), 2.67 (q, /= 7.6 Hz, 2H), 2.53 (t, / = 2.0 Hz, 1H), 1.22 (t, / = 7.6 Hz, 3H); MS (ESI+) m/z 231.1 (M+H)+.
WO 44620 b) (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)prop en-l-one o o o To a stirred on of (£’)(3-ethyl(propyn-l-yloxy)phenyl)acrylic acid (0.28 g, 1.22 mmol, 1.0 equiv.) in dichloromethane (5 mL) at 0°C was added oxalyl de (0.463 g, 3.65 mmol, 3.0 equiv.) and the mixture stirred at 25°C for 10 minutes. The on mixture was concentrated under reduced pressure to give a yellow solid and the residue was dissolved in dichloromethane (4 mL). 3,4-Dihydro-2/7-L4-bcnzoxazinc (0.197g, 1.46mmol, 1.2 equiv.), triethylamine (0.057 g, 0.563 mmol, 2.0 equiv.) and dimethylaminopyridine (0.003 g, 0.028 mmol, 0.1 equiv.) were added at 25°C and the resultant mixture was stirred at 25°C for 12 hours. The reaction was diluted with water (30 mL) and extracted with dichloromethane (4 x 10 mL). The combined organic phase was dried over sodium e and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the desired product as a white solid (48 mg, 47%); NMR (CDCI3, 400 MHz) 5 7.74 (d, / = 15.6 Hz, 1H), 7.34 - 7.32 (m, 2H), 7.21 (d, /= 6.8 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.98 - 6.92 (m, 4H), 4.75 (d, / = 2.4 Hz, 2H), 4.37 (t, / = 4.4 Hz, 2H), 4.08 (t, / = 4.8 Hz, 2H), 2.65 (q, / = 7.6 Hz, 2H), 2.52 (t, / = 2.4 Hz, 1H), 1.20 (t, /= 7.6 Hz, 3H); MS (ESI+) m/z 348.1 (M+H)+; 100% purity, RT 2.42 min (Method 10). -(3-ethyl(propyn-l -yloxy)phenyl)-N-(2-(3-methyl-l 4-triazol-l -yl)phenyl)- acrylamide (114) a) 3-methyl-l-(2-nitrophenyl)-lH-l,2,4-triazolecc* Ty- ocN°2 To a mixture of l-fluoronitrobenzene (1 mL, 12.8 mmol, 1.0 equiv.) and 3-methyl- 177-1,2,4-triazole (1.27 g, 15.3 mmol, 1.2 equiv.) in acetonitrile (20 mL) was added potassium carbonate (5.29 g, 38.3 mmol, 3.0 equiv.) and the mixture was stirred at 60°C for 12 hours. The mixture was cooled to 20°C, diluted with ethyl acetate (20 mL) and filtered. The filtrate was concentrated under reduced pressure to give a residue which was purified by silica gel chromatography (petroleum ether: ethyl acetate 2:1 to 1:1) to give the desired product as a light yellow solid (1.20 g, 46%); ^ NMR (DMSO-d6, 400 MHz) 5 8.96 (s, 1H), 8.12 (d, /= 8.0 Hz, 1H), 7.90 - 7.88 (m, 1H), 7.86 - 7.84 (m, 1H), 7.60 (t,J= 8.0 Hz, 1H), 2.31 (s, 3H). b) 2-(3-methyl-lH-l,2,4-triazol-l-yl)aniline ocN°2 or To a solution of 3-methyl-l-(2-nitrophenyl)-l,2,4-triazole (1.20 g, 5.88 mmol, 1.0 equiv.) in methanol (16 mL) was added Pd/C (0.2 g, 5%) and the mixture was stirred at 20°C under a hydrogen atmosphere for 4 hours. The mixture was ed and the filtrate concentrated under reduced re to give the desired t as light yellow gum which was used directly without further purification (1.00 g); 1H NMR (CDC13, 400 MHz) 5 8.24 (s, 1H), 7.20 (t, J = 8.0 Hz, 1H), 7.15 (d,/= 1.6 Hz, 1H), 6.85 (d, 7 = 2.8 Hz, 1H), 6.83 (d, 7 = 7.6 Hz, 1H), 4.54 (hr. s., 2H), 2.50 (s, 3H). c) (E)(3-ethyl(propyn-l-yloxy)phenyl)-N-(2-(3-methyl-lH-l,2,4-triazol-l- yl)pheny 1) -acrylamide .Nk H Nij ed according to the procedure described for the synthesis of (£)-1 -(2H- benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l-yloxy)phenyl)propen-l-one (113) starting from (C)(3-cthyl(propyn-l-yloxy)phcnyl(acrylic acid and 2-(3-methyl-lH-l,2,4- triazol-1 -yl)aniline (14%); ^ NMR (CDC13, 400 MHz) 5 9.80 (s, 1H), 8.62 (d, 7= 8.4 Hz, 1H), 8.41 (s, 1H), 7.65 (d, 7= 15.6 Hz, 1H), 7.50 - 7.40 (m, 1H), 7.39 - 7.34 (m, 3H), 7.28 - 7.20 (m, 1H), 6.98 (t, 7 = 9.2 Hz, 1H), 6.35 (d, 7 = 15.2 Hz, 1H), 4.76 (d, 7 = 2.4 Hz, 2H), 2.68 (q, 7 = 7.6 Hz, 2H), 2.62 (s, 3H), 2.52 (t, 7 = 2.4 Hz, 1H), 1.23 (t, 7 = 7.6 Hz, 3H); MS (ESI+) m/z 387.2 (M+H)+; 95.8% purity, RT 2.15 min (Method 10). (/?)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)-propen-l-one (115) 'O o a) 2-(2-(dimethylamino)ethoxy)-3,4-dimethoxybenzaldehyde OH / ■0 o Y" 0 'O' '0 To a solution of oxy-3,4-dimethoxybenzaldehyde (3.00 g, 16.5 mmol, 1.0 equiv.) and dimethylaminoethylchloride hydrochloride (2.38g, 16.5 mmol, 1.0 equiv.) in acetonitrile (50 mL) was added potassium carbonate (6.83 g, 49.4 mmol, 3.0 equiv.) and sodium iodide (0.247 g, 1.65 mmol, 0.1 equiv.) and the mixture stirred at 80 °C for 12 hours. The reaction mixture was filtered and the filtrate concentrated under reduced re. The residue was ed by silica gel column chromatography (dichloromethane: methanol 1:0 to 10:1) to provide the desired product as brown oil, (3.20 g) which was used without further purification; ^ NMR , 400 MHz) 8 10.30 (s, 1H), 7.61 (d, / = 8.4 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 4.27 (t, J = 5.6 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 3H), 2.69 (t, J = 5.6 Hz, 2H), 2.31 (s, 6H). b) (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylic acid I I 0 r 0 .0. .0. '0 'OH 0 0 The title compound was prepared according to the procedure described for the synthesis of (£’)(3-ethylpropynoxyphenyl)propenoic acid starting from 2-(2- (dimethylamino)ethoxy)-3,4-dimethoxybenzaldehyde and malonic acid; 'fi NMR (CD3OD, 400 MHz) 5 7.75 (d, /= 16.0 Hz, 1H), 7.42 (d, /= 8.8 Hz, 1H), 6.92 (d, /= 8.8 Hz, 1H), 6.44 (d, / = 16.0 Hz, 1H), 4.28 (t, /= 4.8 Hz, 2H), 3.90 (s, 3H), 3.89 (s, 3H), 3.62 (t, /= 4.8 Hz, 2H), 3.07 (s, c) (E)-l-(2H-benzo[b][l,4]oxazin-4(3H)-yl)(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl) propen-l-one WO 44620 I I / \ o o 0 0 .0. .0.
'OH N T V "O' The title nd was prepared according to the procedure described for the sis of (£’)-l-(2//-benzo[b][l,4]oxazin-4(3//)-yl)(3-ethyl(propyn-l- yloxy)phenyl)propen-l-one (113) starting from -(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylic acid and 3,4-dihydro-2H-benzo[b][l,4]oxazine (11%); H NMR (CD3OD, 400 MHz) 5 7.91 (d,/= 15.6 Hz, 1H), 7.29 (d,/= 8.8 Hz, 2H), 7.15 - 7.12 (m, 2H), 6.95 - 6.93 (m, 2H), 6.83 (d, /= 8.8 Hz, 1H), 4.35 (t, /= 4.8 Hz, 2H), 4.13 (t, /= 5.6 Hz, 2H), 4.04 (t, J = 4.8 Hz, 2H), 3.88 (s, 3H), 3.83 (s, 3H), 2.68 (t, J = 5.6 Hz, 2H), 2.32 (s, 6H). MS (ESI+) m/z 413.2 (M+H)+; 100% purity, RT 1.58 min (Method 10). (/?)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116) I I \ 0 o \ .0. H .0. 0 0^ OH N 'O' o O^ OH A mixture of 2-(2-(dimethylamino)ethoxy)-3,4-dimethoxybenzaldehyde (4.17 g, 16.4 mmol, 1.0 equiv.), 2-(2-carboxyacetamido)benzoic acid (3.99 g, 18.0 mmol, 1.1 equiv.) and piperidine (1.78 mL, 18.0 mmol, 1.1 equiv.) in toluene (100 mL) was heated at 115 °C for 4 hours. The mixture was cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in a minimal amount of methanol, allowed to stand overnight and the resulting solid collected. The solid was washed with methanol, the washings concentrated in vacuo and the residue was purified by silica gel column chromatography (methanol/DCM 2% to %). The product from the column was then combined with the solid and tallized from methanol to afford the title compound as a white solid (4.07 g, 60%). ‘H NMR (400 MHz, DMSO) 5 14.27 (s, 1H), 8.62 - 8.60 (m, 1H), 8.10 (dd, /= 7.8 Hz, /= 1.5 Hz, 1H), 7.97 (d, J = 16.6 Hz, 1H), 7.67 (d, /= 8.8 Hz, 1H), 7.45 - 7.39 (m, 1H), 7.09 - 7.04 (m, 1H), 6.99 (d, /= 9.1 Hz, 1H), 6.56 (d, / = 17.0 Hz, 1H), 4.42 - 4.37 (m, 2H), 3.91 (s, 3H), 3.85 (s, 3H), 3.66 (dd, / = 4.4 Hz , 7 = 4.4 Hz, 2H), 3.01 (s, 6H). MS (ESf) m/z 415.4 (M+H)+: 99.0 % purity, RT 2.60 min (Method 2). (/?)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic add (117) o OH a) 2-(2-Carboxyacetamido)chlorobenzoic add Cl Cl H02C^hN O' o OH A mixture of methyl 2-aminochlorobenzoate (0.50 g, 2.69 mmol, 1.0 equiv.) and NaOH (0.14 g, 3.58 mmol, 1.3 equiv.) in ethanol (5 mL) and water (5 mL) was heated at reflux for 1.5 hours and then cooled to room temperature. The pH was adjusted to pH 1 with 2N hydrochloric acid and the resulting precipitate was isolated by tion, washed with water then dried under suction and used without further purification.
The solid (0.37 g, 2.16 mmol, 1.05 equiv.) was suspended in toluene (5 mL) and 2,2- dimethyl-l,3-dioxane-4,6-dione (0.295 g, 2.05 mmol, 1.0 equiv.) was added. The e was heated at reflux for 6 hours at which point a further n of 2,2-dimethyl-l,3-dioxane-4,6- dione (0.016 g, 0.11 mmol) was added. After a further 30 minutes at reflux the mixture was cooled and the resulting precipitate was isolated by filtration, washed with toluene and dried under suction to give the title compound as a cream solid (0.49 g, 89%). ^ NMR (400 MHz, DMSO): 5, ppm 12.95 - 12.95 (m, 1H), 11.47 (s, 1H), 8.64 (d, 7= 2.3 Hz, 1H), 8.05 (d, 7= 8.6 Hz, 1H), 7.33 - 7.29 (m, 1H), 3.57 (s, 2H). MS (ESI+) m/z 258 (M+H)+. b) (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4- dimethoxyphenyl)acrylamido)benzoic acid Cl \ Cl H°2C^N 0 H N cr OH H 'O' O^ OH The title nd was prepared according to the procedure for (£’)(3-(2-(2- (dimethylamino)ethoxy)methoxy(propyn-l-yloxy)phenyl)acrylamido)-benzoic acid (78) starting from 2-(2-carboxyacetamido)chlorobenzoic acid and 2-(2-(dimethylamino)ethoxy)- 3,4-dimethoxybenzaldehyde (50%); ‘H NMR (400 MHz, CDC13): 5 ppm 7.51 (1H, d, J=15.4 Hz), 7.10 - 7.07 (1H, m), 7.06 - 7.02 (1H, m), 6.97 (1H, d, / = 8.3 Hz), 6.41 (1H, d, / = 14.9 Hz), 6.00 - 5.93 (1H, m), 4.78 (2H, d, /= 2.5 Hz), 3.89 (3H, s), 3.77 - 3.66 (1H, m), 2.68 - 2.59 (1H, m), 2.54 - 2.51 (1H, m), 2.01 - 1.96 (2H, m), 1.77 - 1.66 (2H, m), 1.33 - 1.19 (4H, m); MS: (ESI+) m/z 329.2(M+H)+99.01% purity, RT = 2.87min., d 3). (/?)-l-(2H-benzo[b][l,4]oxazin-4(3//)-yl)(3-methoxy((l-methylpyrrolidin )phenyl)propen- 1-one (118) a) (E)-methyl 3-(3-methoxy((l -methylpyrrolidinyl)oxy)phenyl)acrylate I o I o o 0 0 ■O' HO' 'O' To a solution of methyl (£’)(4-hydroxymethoxyphenyl)propenoate (2.00 g, 9.61 mmol, 1.0 equiv.), l-methylpyrrolidinol (1.17 g, 11.5 mmol, 1.2 equiv.) and triphenylphosphine (3.02 g, 11.53 mmol, 1.20 equiv.) in tetrahydrofuran (10 mL) at 0°C was added diisopropylazodicarboxylate (2.33 g, 11.5 mmol, 1.2 equiv.) over 30 minutes. The reaction mixture was diluted with IN hloric acid (50 mL) and extracted with ethyl acetate (3 x 50 mL), the aqueous layer was adjusted to pH = 8 with IN sodium hydroxide on and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product as a yellow oil (2.50 g, 89%) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 8 7.62 (d, /= 16.0 Hz, 1H), 7.05 (d, /= 8.0 Hz, 1H), 7.04 (s, 1H), 7.76 (d, /= 8.0 Hz, 1H), 6.30 (d, J= 16.0 Hz, 1H), 4.89 - 4.85 (m, 1H), 3.87 (s, 3H), 3.79 (s, 3H), 2.95 - 2.92 (m, 1H), 2.80 - 2.76 (m, 2H), 2.55 - 2.53 (m, 1H), 2.39 (s, 3H), 2.38 - 2.35 (m, 1H), 2.05 - 2.01 (m, 1H). b) (E)(3-methoxy((l-methylpyrrolidinyl)oxy)phenyl)acrylic acid I o I 0 0 o 'O' 'OH —N. —N, 'O' 'O' To a mixture of (Lj-methyl 3-(3-methoxy((l-methylpyrrolidin yl)oxy)phenyl)acrylate (1.50 g, 5.15 mmol, 1.0 equiv.) in methanol (15 mL) and water (2 mL) was added lithium hydroxide (0.247 g, 10.3 mmol, 2.0 equiv.) and the mixture stirred at 25°C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water (100 mL) and the mixture extracted with dichloromethane (30 mL x3). The aqueous phase was adjusted to pH=5 with IN hydrochloric acid and concentrated under reduced pressure to get the desired product as a brown oil, which was used directly without further purification (1.50 g); NMR (CD3OD, 400 MHz) 5 7.39 (d, /= 16.0 Hz, 1H), 7.19 (d, / = 2.0 Hz, 1H), 7.09 (dd, / = 8.0 Hz, / = 2.0 Hz, 1H), 6.97 (d, / = 8.0 Hz, 1H), 6.40 (d, / = 16.0 Hz, 1H), 5.14 - 5.12 (m, 1H), 3.88 (s, 3H), 3.53 - 3.49 (m, 3H), 3.31 - 3.30 (m, 1H), 2.90 (s, 3H), 2.47 - 2.43 (m, 1H), 2.54 - 2.27 (m, 1H). c) (2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-methoxy((l-methylpyrrolidin )phenyl)-propen-l-one I o o 0 .0.
'O' N ‘O' o The title compound was prepared ing to the procedure described for the synthesis of -(2H-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l- yloxy)phenyl)propen-l-one (113) starting from (£)(3-methoxy((l-methylpyrrohdin )phenyl)acrylic acid and 3,4-dihydro-2H-benzo[b][l,4]oxazine (9%); H NMR (CDCI3, 400 MHz) 5 7.64 (d, / = 15.2 Hz, 1H), 7.13 (d, / = 2.0 Hz, 1H), 7.09 - 7.05 (m, 1H), 7.04 - 6.98 (m, 1H), 6.91 (d, /= 1.6 Hz, 1H), 6.88 (t, /= 6.8 Hz, 1H), 6.83 - 6.81 (m, 2H), 6.71 (d, /= 8.0 Hz, 1H), 4.80 - 4.80 (m, 1H), 4.29 (t, /= 4.8 Hz, 2H), 4.00 (t, /= 4.8 Hz, 2H), 3.78 (s, 3H), 2.89 - 2.87 (m, 1H), 2.77 - 2.74 (m, 2H), 2.52 - 2.47 (m, 1H), 2.35 (s, 3H), 2.27 - 2.23 (m, 1H), 1.99 - 1.96 (m, 1H); MS (ESI+) m/z 395.2 (M+H)+; 92.8% purity, RT 2.59 min (Method 8). (2//-benzo[b][l,4]oxazin-4(3//)-yl)(2-(3-methoxy(propyn-l-yloxy) phenyl) cyclopropyl) methanone (119) a) methyl 2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylate 0 0 .0. .0.
‘O' 0 To a solution of trimethylsulfoxonium iodide (1.34 g, 6.09 mmol, 1.5 ) in dimethylsulfoxide (10 ml) at 0°C was added sodium hydride (0.107 g, 4.47 mmol, 1.1 equiv.) and the mixture stirred at 25°C for 30 minutes. Methyl (£’)(3-methoxyprop ynoxy-phenyl)propenoate (1.00 g, 4.06 mmol, 1.0 equiv.) was then added and the reaction stirred at 25°C for 12 hours. The reaction mixture was diluted with water (30 mL) and extracted with ethyl acetate (5 x 10 mL). The combined organic phase was washed with water (5 x 30 ml), dried over sodium sulfate and concentrated under reduced pressure to give the desired product as a yellow oil (1.00 g) which was used without further purification; ^ NMR (CDCI3, 400 MHz) 8 6.95 (d, /= 8.1 Hz, 1H), 6.66 - 6.63 (m, 2H), 4.75 (d, 7= 2.4 Hz, 2H), 3.87 (s, 3H), 3.73 (s, 3H), 2.52 (d, 7 = 2.4 Hz, 1H), 2.51 -2.49 (m, 1H), 1.65 - 1.59 (m, 1H), 1.58 - 1.56 (m, 1H), 1.30- 1.27 (m, 1H). b) 2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylic acid 0 0 .0. o .0.
To a mixture of methyl ethoxy(propyn-l- yloxy)phenyl)cyclopropanecarboxylate (1.00 g, 3.86 mmol, 1.0 equiv.) in methanol (15 mL) and water (2 mL) was added lithium hydroxide (0.185 g, 7.72 mmol, 2.0 equiv.) and the reaction was stirred at 25°C for 12 hours. The reaction was trated under reduced pressure to give a residue which was d with water (100 mL) and the aqueous mixture extracted with dichloromethane (3 x 30 mL). The aqueous phase was adjusted to pH 5 with IN hydrochloric acid and concentrated under reduced pressure to get the d product as brown oil, which was used directly without r purification (0.4 g, 42%); ^ NMR , 400 MHz) 8 6.96 (d, 7 = 8.4 Hz, 1H), 6.69 (d, 7 = 2.4 Hz, 1H), 6.65 (dd, 7 = 8.4 Hz, 7 = 2.0 Hz, 1H), 4.74 (d, 7 = 2.4 Hz, 2H), 3.90 (s, 3H), 2.58 - 2.51 (m, 1H), 2.50 (t, 7= 2.4 Hz, 1H), 1.88 - 1.86 (m, 1H), 1.65 - 1.62 (m, 1H), 1.29 - 1.25 (m, 1H). c) (2H-benzo[b][l,4]oxazin-4(3H)-yl)(2-(3-methoxy(propyn-l-yloxy) phenyl) cyclopropyl) methanone o o .0. .0.
"OH N T ^0 k/O The title compound was prepared ing to the procedure described for the synthesis of (£,)-l-(2//-benzo[b][l,4]oxazin-4(3H)-yl)(3-ethyl(propyn-l- yloxy)phenyl)propen-l-one (113) starting from 2-(3-methoxy(propyn-lyloxy )phenyl)cyclopropanecarboxylic acid and 3,4-dihydro-2H-benzo[b][l,4]oxazine (9%); H NMR (CDCI3, 400 MHz) 5 7.27 - 7.26 (m, 1H), 7.04 - 7.02 (m, 1H), 6.96 - 6.91 (m, 2H), 6.75 - 6.70 (m, 1H), 6.64 - 6.63 (m, 1H), 6.62 - 6.61 (m, 1H), 4.74 (d, / = 2.4 Hz, 2H), 4.36 - 4.30 (m, 2H), 4.22 - 4.21 (m, 1H), 3.85 - 3.84 (m, 4H), 2.63 - 2.59 (m, 1H), 2.51 (t, / = 2.0 Hz, 1H), 2.40 - 2.39 (m, 1H), 1.83 - 1.79 (m, 1H), 1.33 - 1.30 (m, 1H); MS (ESI+) m/z 364.1 (M+H)+; 99.7% , RT 2.12 min (Method 9).
(/?)-/V-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (120) o K& a) (E)-tert-butyl 4-(2-methoxy(3-methoxyoxoprop-l-en-l-yl)phenyl)-5,6- dihydropyridine-1 (2H) -carboxylate o aO' .0. .0. 'O' "O' B'0 Br' .N Boc -N A mixture of methyl (£’)(4-bromomethoxyphenyl)propenoate (0.5 g, 1.84 mmol, 1.0 equiv.), / "O' "OH Boo"N Boc^ The title compound was prepared according to the ure bed for the synthesis of2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylic acid starting from (Tj-tcrt-hutyl 4-(2-methoxy(3-methoxyoxoprop-l-en-l-yl)phenyl)-5,6- dihydropyridine-1 (2H)-carboxylate; NMR (CD3OD, 400 MHz) 5 7.36 (d, / = 15.6 Hz, 1H), 7.13 - 7.06 (m, 3H), 6.49 (d,J= 16.0 Hz, 1H), 5.77 - 5.76 (m, 1H), 4.04 - 4.01 (m, 2H), 3.84 (s, 3H), 3.62 - 3.58 (m, 2H), 2.49 - 2.45 (m, 2H), 1.47 (s, 9H); MS (ESI+) m/z 382.1 (M+Na)+. c) (E)-N-(4-fluorophenyl)(3-methoxy(l,2,3,6-tetrahydropyridin yl)phenyl)acrylamide "OH .0. vOr Boc"N HN.
To a solution of (£,)[4-(l-/er/-butoxycarbonyl-3,6-dihydro-27/-pyridinyl) methoxy-phenyl]propenoic acid (0.1 g, 0.278 mmol, 1.0 equiv.) in A/.iV-di methyl form amide (5 mL) was added HATU (0.159 g, 0.417 mmol, 1.5 equiv.) and ropylethylamine (0.108 g, 0.835 mmol, 3.0 equiv.) and the resultant mixture was stirred at 20°C for 1 hour. Then 4- fluoroaniline (0.037 g, 0.334 mmol, 1.2 equiv.) was added and the mixture was stirred for 3 hours at 20°C. The reaction mixture was diluted with ethyl acetate (15 mL) and washed with water (3x10 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting yellow oil was dissolved in dichloromethane (5 mL) and treated with trifluoroacetic acid (0.378 g, 3.31 mmol, 10.0 equiv.) and the resulting solution was d at 20°C for 2 hours. The mixture was concentrated under reduced re to give a residue which was purified by preparative HPLC to give the desired product as a yellow solid (0.042 g, 27%); 1H NMR (CD3OD, 400 MHz) 5 7.69 - 7.65 (m, 2H), 7.62 (s, 1H), 7.23 - 7.21 (m, 3H), 7.10 - 7.06 (m, 2H), 6.80 (d, /= 16.0 Hz, 1H), 5.88 - 5.87 (m, 1H), 3.89 (s, 3H), 3.83 (d, J = 2.4 Hz, 2H), 3.43 - 3.40 (m, 2H), 2.98 - 2.78 (m, 2H); MS (ESI+) m/z 353.1 (M+H)+; 98.3% purity, RT 2.47 min (Method 11). cyanophenyl)(3-methoxy(l,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121) wCN .0. a) methyl 2-(4-bromomethoxyphenyl)cyclopropanecarboxylate o o .0. .0. 0 ‘O' Br­ er The title compound was prepared ing to the procedure described for the synthesis of methyl 2-(3-methoxy(propyn-l-yloxy)phenyl)cyclopropanecarboxylate starting from (^-methyl 3-(4-bromomethoxyphenyl)acrylate; 'h NMR (CDCI3,400 MHz) 8 7.42 (d, J = 8.4 Hz, 1H), 6.67 (d, / = 8.4 Hz, 1H), 6.55 (dd, /= 8.4 Hz, / = 2.0 Hz, 1H), 3.89 (s, 3H), 3.73 (s, 3H), 2.52 - 2.48 (m, 1H), 1.91 - 1.89 (m, 1H), 1.63 - 1.59 (m, 1H), 1.33 - 1.31 (m, b) tert-butyl 4-(2-methoxy(2-(methoxycarbonyl)cyclopropyl)phenyl)-5,6- dihydropyridine-1 (2H) -carboxylate o .0. .0. "O' The title compound was prepared according to the procedure described for the synthesis of ert-butyl 4-(2-methoxy(3-methoxyoxoprop-l-en-l-yl)phenyl)-5,6- dihydropyridinc-1 (2/7)-carboxylatc starting from methyl 2-(4-bromo methoxyphenyl)cyclopropanecarboxylate and / 'OH 0 'O' 'O' To a solution of (T)(2-(2-(di methyl ami no)ethoxy)-3,4-dimethoxyphenyl)acry lie acid (1.50 g, 5.08 mmol, 1.0 equiv.) in methanol (20 mL) was added copper sulfate (1.49 g, 15.2 mmol, 3.0 equiv.) at 0°C and the resultant mixture d at 20°C for 3 hours. The on mixture was adjusted to pH 7 with IN hydrochloric acid and concentrated under reduced pressure. The residue was diluted with ethyl acetate (20 mL) and washed with water (20 mL x3).
The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced re to give the desired product as yellow oil (1.35 g) which was used without r purification; 1H NMR (CDCI3, 400 MHz) 5 7.96 (d, J = 16.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 6.68 (d /= 8.4 Hz, 1H), 6.40 (d, /= 16.4 Hz, 1H), 4.13 (t, /= 6.0 Hz, 2H), 3.90 (s, 3H), 3.88 (s, 3H), 3.33 (s, 3H), 2.73 (t, /= 5.6 Hz, 2H), 2.35 (s, 6H). b) 2-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane- 1-carboxamide I I /' \ •O. .0.
'O' w "O' o The title compound was prepared as the trifluoroacetic acid salt according to the procedure described for the synthesis of (2/7-bcnzo[b][ azin-4(3/7)-yl)(2-(3-mcthoxy (propyn-l-yloxy)phenyl) cyclopropyl)methanone (119) starting from (Lj-methyl 3-(2-(2- (dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylate and 4-fluoroaniline; 'h NMR (CD3OD, 400 MHz) 5 7.59 - 7.56 (m, 2H), 7.06 (t, /= 8.8 Hz, 2H), 6.81 (d, /= 8.8 Hz,lH), 6.73 (d,/ = 8.4 Hz, 1H), 4.31 - 4.26 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.53 (t, /= 2.4 Hz, 2H), 3.00 (s, 6H), 2.67 - 2.65 (m, 1H), 1.90 - 1.88 (m, 1H), 1.55 - 1.53 (m, 1H), 1.40 - 1.38 (m, 1H); MS (ESI+) m/z 403.2 (M+H)+; 96.7% purity, RT 2.48 min (Method 11).
Ex Structure Data Method 123 1H NMR (CDCL, 400 MHz) 5 8.49 0 r Prepared according N (t, J= 3.2 Hz, 1H), 7.73 (d, J= 15.6 to the method for F Hz, 1H), 7.48 (s, 1H), 7.42 - 7.38 113 starting from 2- (£)(3-ethyl(propyn-l- (m, 2H), 7.17 - 7.15 (m, 1H), 7.12 - fluoroaniline phenyl)-N-(2- 7.10 (m, 1H), 7.10 - 7.09 (m, 1H), fluorophenyl) acrylamide 6.98 (d, J = 8.4 Hz, 1H), 6.47 (d, J = .2 Hz, 1H), 4.77 (d, J= 2.4 Hz, 2H), 2.68 (q, /= 7.2 Hz, 2H), 2.53 (t, 7=2.4 Hz, 1H), 1.24 (t, 7=7.2 Hz, 3H); MS (ESI+) m/z 324.1 (M+H)+; 100% , RT 2.33 min w (Method 10)_____________________ 124 CN 1H NMR (CDC13, 400 MHz) 5 7.77 Prepared according - 7.73 (m, 3H), 7.64 (d, 7= 8.8 Hz, to the method for <0^0 2H), 7.44 - 7.38 (m, 3H), 6.98 (d, 7 113 ng from 4- = 8.0 Hz, 1H), 6.43 (d, 7= 15.6 Hz, aminobenzonitrile (£’)-/V-(4-cyanophcnyl)(3- 1H), 4.77 (d, 7= 2.4 Hz, 2H), 2.68 ethyl(propyn-1 - (q, 7= 6.8 Hz, 2H), 2.54 (t, 7= 2.4 yloxy)phenyl)acrylamide Hz, 1H), 1.23 (t, 7= 6.8 Hz, 3H); MS (ESI+) m/z 331.2 (M+H)+; 92% w purity, RT 2.33 min (Method 10) 125 1H NMR , 400 MHz) 5 7.71 Prepared according (d, 7= 15.2 Hz, 1H), 7.58 (s, 2H), to the method for I H 7.38 - 7.35 (m, 3H), 7.05 (t, 7= 8.4 113 starting from 4- Hz, 2H), 6.95 (d, 7= 8.4 Hz, 1H), fluoroaniline (£)(3-ethyl(propyn-l- 6.43 (d, 7= 15.6 Hz, 1H), 4.76 (d, 7 yloxy)phenyl)-N-(4- = 2.4Hz, 2H), 2.66 (q, 7= 7.6 Hz, fluorophenyl) acrylamide 2H), 2.53 (t, 7= 2.4 Hz, 1H), 1.22 (t, 7= 7.6 Hz, 3H); MS (ESI+) m/z 324.1 (M+H)+; 96.5% purity, RT 2.32 min (Method 9)_____________ 126 o 1H NMR (CDCI3, 400 MHz) 5 7.96 Prepared according N Vi (d, 7= 16.0 Hz, 1H), 7.62 (d, 7= 8.0 to the method for <0^0 Nsa Hz, 1H), 7.48 - 7.46 (m, 3H), 7.41 113 ng from (£)(3-ethyl(propyn-l- (t, 7= 8.0 Hz, 1H), 7.24 (d, 7= 7.6 lH-indazolol yloxy)phenyl) -1 -(3 -hydroxy-1H- Hz, 1H), 7.01 (d, 7 = 8.0 Hz, 1H), indazol-1 -yl)propen-1 -one 6.65 (d, 7= 13.2 Hz, 1H), 4.79 (d, 7 = 2.4 Hz, 2H), 2.70 (q, 7= 7.6 Hz, 2.4 Hz, 2H), 2.55 (t, 7= 2.4 Hz, 1H), 1.25 (t, 7= 7.6 Hz, 3H); MS (ESI+) m/z 347.1 (M+H)+; 96.8% purity, RT 2.97 min (Method 12) 127 I 1H NMR (CD3OD, 400 MHz) 5 8.04 Prepared according - 8.03 (m, 1H), 7.94 (d, 7= 15.6 Hz, to the method for 0 1H), 7.42 (d, 7= 8.8 Hz, 1H), 7.24 - 118 starting from 2- N 7.13 (m, 3H), 6.89 (s, 1H), 6.85 (d, fluoroaniline ‘O' 7= 8.0 Hz, 1H), 4.16 (d, 7= 5.6 Hz, (£)(2-(2- 2H), 3.90 (s, 3H), 3.85 (s, 3H), 2.83 (dimethylamino)ethoxy)-3,4- (t, 7= 5.6 Hz, 2H), 2.38 (s, 6H); MS dimethoxyphenyl)-N-(2- (ESI+) m/z 389.2 (M+H)+; 100% fluorophenyl) acrylamide purity, RT 1.44 min (Method 10) 128 I iH NMR (CD3OD, 400 MHz) 5 7.90 Prepared according \ (d, /= 15.6 Hz, 1H), 7.68 - 7.66 (m, to the method for 2H), 7.48 (d, /= 8.8 Hz, 1H), 7.08 115 starting from 4- /0. (t, / = 8.4 Hz, 2H), 6.95 (d, / = 8.8 fluoroaniline \ H O Hz, 1H), 6.72 (d, /= 15.6 Hz, 1H), (£)(2-(2- 4.30 (t, J= 4.8 Hz, 2H), 3.92 (s, (dimethylamino)ethoxy)-3,4- 3H), 3.91 (s, 3H), 3.65 (t, 7=5.2 dimethoxyphenyl)-/V-(4- Hz, 2H), 3.10 (s, 6H); MS (ESI+) fluorophenyl)acrylamide m/z 389.2 (M+H)+; 100% purity, oroacetic acid salt RT 1.46 min d 10) 129 I 1H NMR (CD3OD, 400 MHz) 5 7.96 Prepared according \ (d, 7= 16.0 Hz, 1H), 7.88 (d, 7= 8.8 to the method for 115 starting from 4- Hz, 2H), 7.70 (d, 7= 8.8 Hz, 2H), /0. W H 7.50 (d, 7 = 8.8 Hz, 1H), 6.97 (d, 7 = aminobenzonitrile O 8.8 Hz, 1H), 6.74 (d, 7 = 16.0 Hz, (£’)-/V-(4-cyanophcnyl)(2-(2- 1H), 4.31 (t, 7= 4.8 Hz, 2H), 3.93 hylamino)ethoxy)-3,4- (s, 3H), 3.91 (s, 3H), 3.66 (t, 7= 4.8 dimethoxyphenyl)acrylamide Hz, 2H), 3.10 (s, 6H); MS (ESI+) trifluoroacetic acid salt m/z 396.2 (M+H)+; 97.5% purity, RT 1.44 min (Method 10) 130 1H NMR (CD3OD, 400 MHz) 5 8.11 0 Prepared according - 8.09 (m, 1H), 7.64 (d, 7= 15.6 Hz, fCXo N to the method for F 1H), 7.26 - 7.25 (m, 1H), 7.26 - 7.17 118 starting from 2- (£0-A^-(2-fluorophenyl)(3- (m, 4H), 6.96 (d, 7= 7.6 Hz, 1H), fluoroaniline methoxy(( 1 lpyrrolidin- 6.94 (d, 7= 15.6 Hz, 1H), 5.03 - 3-yl)oxy)phenyl)acrylamide 5.02 (m, 1H), 3.90 (s, 3H), 3.09 - 3.04 (m, 3H), 2.77 - 2.75 (m, 1H), 2.56 (s, 3H), 2.44 - 2.37 (m, 1H), 2.13-2.11 (m, 1H); MS (ESI+) m/z 371.2 (M+H)+; 98.1% , RT ixr 2.48 min (Method 8) 131 iH NMR (CD3OD, 400 MHz) 5 7.96 Prepared according - 7.60 (m, 2H), 7.72 - 7.58 (m, 3H), to the method for .N 'O’ 7.28 (s, 1H), 7.21 (d, 7= 8.0 Hz, 118 starting from 4- (£0-A^-(4-cyanophenyl)(3- 1H), 7.04 (d, 7= 7.2 Hz, 1H), 6.71 aminobenzonitrile methoxy(( 1 -methylpyrrolidin- (d, 7= 15.6 Hz, 1H), 5.30 - 5.16 (m, 3-yl)oxy)phenyl)acrylamide 1H), 3.95 - 3.70 (m, 5H), 3.48 - 3.31 trifluoroacetic acid salt (m, 1H), 3.30 - 3.17 (m, 1H), 3.01 (s, 3H), 2.65 - 2.21 (m, 2H); MS (ESI+) m/z 378.2 (M+H)+; 100% purity, RT 1.44 min (Method 10) 132 nXT iH NMR (CD3OD, 400 MHz) 5 7.70 Prepared according o - 7.65 (m, 2H), 7.59 (d, 7 = 15.6 Hz, to the method for N 1H), 7.26 - 7.25 (m, 1H), 7.10 - 7.09 118 starting from 4- (£’)-/V-(4-fluoi'ophcnyl)(3- (m, 1H), 7.07 - 7.04 (m, 3H), 6.72 fluoroaniline y(( 1 -methylpyrrolidin- (d, 7= 15.6 Hz, 1H), 5.25 - 5.23 (m, 3-yl)oxy)phenyl)acrylamide 1H), 3.93 - 3.88 (m, 5H), 3.45 - 3.10 trifluoroacetic acid salt (m, 1H), 3.33 - 3.32 (m, 1H), 3.24 - 3.03 (m, 3H), 2.33 - 2.26 (m, 2H); MS (ESI+) m/z 371.2 (M+H)+; 100% purity, RT 1.45 min (Method 133 w 1H NMR (CDC13, 400 MHz) 5 7.58 Prepared according .0. (s, 1H), 7.52 - 7.48 (m, 2H), 7.01 (d, to the method for H J= 8.4 Hz, 2H), 6.94 (d, /= 8.0 Hz, 119 starting from 4- 1H), 6.65 (d, /= 8.4 Hz, 2H), 4.74 fluoroaniline /V-(4-fluorophenyl)(3- (d, /= 2.4 Hz, 2H), 3.82 (s, 3H), y(propyn-1 - 2.55 - 2.53 (m, 1H), 2.50 (t, /= 2.4 yloxy)phenyl)cyclopropanecarbo Hz, 1H), 1.73 - 1.68 (m, 2H), 1.34 - xamide 1.31 (m, 1H); MS (ESI+) m/z 340.3 ; 100% purity, RT 2.11 min (Method 10) 134 o 1H NMR (CDCI3, 400 MHz) 5 8.43 Prepared according (hr. s, 1H), 7.70 (d, /= 6.8 Hz, 1H), to the method for 7.62 (d, /= 8.0 Hz, 1H), 7.39 (d, / = 119 starting from (3 -hydroxy-1 H-indazol-1 -yl) (2- 7.2 Hz, 1H), 6.97 (d, /= 8.0 Hz, lH-indazolol (3-methoxy(propyn-1 - 1H), 6.79 - 6.77 (m, 2H), 4.74 (d, J yloxy)phenyl)cyclopropyl) = 2.4 Hz, 2H), 3.84 (s, 3H), 3.04 (s, methanone 1H), 2.82 - 2.77 (m, 1H), 2.48 (t, / = 2.4 H, 1H), 1.91 - 1.89 (m, 1H), 1.58 - 1.55 (m, 1H); MS (ESI+) m/z 363.1 (M+H)+; 385.1 (M+Na)+; 97.9% purity, RT 2.94 min (Method 135 CN 1H NMR (CDCI3, 400 MHz) 5 7.78 ed according 0 K& (s, 1H), 7.68 (d, /= 8.8 Hz, 2H), to the method for H 7.61 (d, / = 8.8 Hz, 2H), 6.97 (d, / = 119 starting from 4- 8.4 Hz, 1H), 6.65 - 6.64 (m, 2H), aminobenzonitrile /V-(4-cyanophenyl)(3 - 4.75 (d, /= 2.4 Hz, 2H), 3.82 (s, methoxy(propyn-1 - 3H), 2.63 - 2.50 (m, 1H), 2.49 (t, / = yloxy)phenyl)cyclopropanecarbo 2.4 Hz, 1H), 1.61-1.40 (m, 2H), xamide 1.45 - 1.34 (m, 1H); MS (ESI+) m/z 347.1 ; 98.6% purity, RT 136 w 2.04 min (Method 9) 1H NMR (CDCI3, 400 MHz) 5 7.59 Prepared ing -7.51 (m, 3H), 7.02 (d, 7=8.8 Hz, to the method for H 2H), 6.76 (d, 7= 8.4 Hz, 1H), 6.70 119 starting from /N 'O' /V-(4-fluorophenyl)(3- (s, 1H), 6.63 (d, 7= 1.6 Hz, 1H), (Ej-mcthyl 3-(3- methoxy(( 1 -methylpyrrolidin- 4.89 - 4.85 (m, 1H), 3.84 (s, 3H), methoxy((l- 3-yl)oxy)phenyl)cyclopropane- 3.30 - 3.25 (m, 1H), 2.94 - 2.90 (m, methylpyrrolidin-3 - 1-carboxamide 3H), 2.60 - 2.53 (m, 4H), 2.31 - 2.28 yl)oxy)phenyl)acryl (m, 1H), 2.20 - 2.15 (m, 1H), 1.71 - ate and 4- 1.60 (m, 2H), 1.34 - 1.32 (m, 1H); fluoroaniline MS (ESI+) m/z 385.1 (M+H)+; 96.4% purity, RT 1.56 min (Method 137 CN 1H NMR (CD3OD, 400 MHz) 5 7.78 Prepared according .0. w (d, 7= 8.8 Hz, 2H), 7.70 - 7.65 (m, to the method for .N ‘0‘ 2H), 6.94 (d, 7= 8.0 Hz, 1H), 6.87 119 starting from A^-(4-cyanophenyl)(3- (s, 1H), 6.75 - 6.73 (m, 1H), 5.08 (s, (Ej-mcthyl 3-(3- methoxy(( 1 -methylpyrrolidin- 1H), 3.91 (d, J= 8.4 Hz 1H), 3.86 methoxy((l- 3-yl)oxy)phenyl)cyclopropane- (s, 3H), 3.43 - 3.40 (m, 1H), 3.25 - methylpyrrolidin-3 - 1-carboxamide 3.18 (m, 1H), 3.10-3.00 (m, 4H), yl)oxy)phenyl)acryl 2.50 - 2.48 (m, 1H), 2.35 -2.15 (m, ate and 4- 2H), 2.05 - 2.03 (m, 1H), 1.61 - 1.59 aminobenzonitrile (m, 1H), 1.39- 1.30 (m, 1H) ; MS (ESI+) m/z 392.2 (M+H)+; 94.5% purity, RT 2.72 min (Method 12) 138 o iH NMR (CD3OD, 400 MHz) 5 7.94 Prepared according N - 7.92 (m, 1H), 7.17 - 7.14 (m, 3H), to the method for N "O' 6.94 (d, J= 7.2 Hz, 1H), 6.88 (s, 119 starting from /V-(2-fluorophenyl)(3- 1H), 6.75 (d, J= 8.0 Hz, 1H), 5.10 - (Ej-mcthyl 3-(3- methoxy(( 1 -methylpyrrolidin- 5.09 (m, 1H), 3.93 - 3.87 (m, 5H), methoxy((l- 3-yl)oxy)phenyl)cyclopropane 3.41 - 3.42 (m, 1H), 3.27 - 3.17 (m, methylpyrrolidin-3 - carboxamide 1H), 3.10 - 3.00 (m, 3H), 2.50 - 2.47 yl)oxy)phenyl)acryl (m, 2H), 2.30 - 2.19 (m, 2H), 1.60 - ate and 2- 1.57 (m, 1H), 1.37 - 1.33 (m, 1H) ; fluoroaniline MS (ESI+) m/z 385.2 (M+H)+; 96.5% purity, RT 2.4 min (Method 139 CN 1H NMR (CD3OD, 400 MHz) 5 Prepared according .0. w 7.88 - 7.86 (m, 2H), 7.71 - 7.67 (m, to the method for H 3H), 7.26 - 7.22 (m, 3H), 6.82 (d, J 120 starting from 4- HN = 15.6 Hz, 1H), 5.89 (s, 1H), 3.90 aminobenzonitrile.
(£’)-/V-(4-cyanophcnyl)(3- (s, 3H), 3.83 (d, J= 2.8 Hz, 2H), y(l,2,3,6- 3.42 (t, J= 6.0 Hz, 2H), 2.86 - 2.79 tetrahydropyridin (m, 2H); MS (ESI+) m/z 360.3 yl)phenyl) acrylamide (M+H)+; 98.2% , RT 1.61 trifluoroacetic acid salt min (Method 9) 140 0 1H NMR (CD3OD, 400 MHz) 5 ed according N 8.69 (s, 1H), 7.97 (d, J= 7.6 Hz, to the method for 1H), 7.61 - 7.53 (m, 3H), 7.39 - 7.38 120 starting from 2- HN (m, 1H), 7.22 - 7.18 (m, 3H), 6.75 hyl-lH- (3-methoxy(l,2,3,6- (d, /= 15.6 Hz, 1H), 5.87 (t, /= 1.6 1,2,4-triazol-ltetrahydropyridinyl )phenyl)- Hz, 1H), 3.87 (s, 3H), 3.83 (d, / = yl) aniline.
/V-(2-(3-methyl-1H-1,2,4-triazol- 2.8 Hz, 2H), 3.42 (t, /= 6.0 Hz, 1 -yl)phenyl) acrylamide 2H), 2.78 - 2.76 (m, 2H), 2.46 (s, trifluoroacetic acid salt 3H); MS (ESI+) m/z 416.3 (M+H)+; 100% purity, RT 2.26 min (Method 141 o 1H NMR (CD3OD, 400 MHz) 5 Prepared according N 8.09 (t, /= 1.2 Hz, 1H), 7.68 (d, J = to the method for F 15.6 Hz, 1H), 7.24 - 7.17 (m, 6H), 120 starting from 2- HN 6.67 (d, J= 15.6 Hz, 1H), 5.89 (s, fluoroaniline V-(2-fluoi'ophcnyl)(3- 1H), 3.90 (s, 3H), 3.84 (d, /= 2.0 methoxy(l,2,3,6- Hz, 2H), 3.43 (t, /= 6.0 Hz, 2H), tetrahydropyridin 2.80 - 2.78 (m, 2H); MS (ESI+) m/z yl)phenyl)acrylamide 353.2 ; 100% purity, RT 2.52 min (Method 8)_____________ 142 o 1H NMR (CD3OD, 400 MHz) 5 Prepared according N KJ 8.44 (d, J= 8.4 Hz, 1H), 7.90 - 7.78 to the method for OH (m, 2H), 7.78 (d, J= 7.6 Hz, 1H), 120 starting 7.63 - 7.59 (m, 1H), 7.43 - 7.40 (m, fromlH-indazol (E)-1 -(3 -hydroxy-1 H-indazol-1 - 1H), 7.35 - 7.32 (m, 1H), 7.31 - 7.29 ol yl)(3-methoxy(l,2,3,6- (m, 1H), 7.29 - 7.27 (m, 1H), 5.91 ydropyridin (t, 7=2.0 Hz, 1H), 3.93 (s, 3H), yl)phenyl)propen-1 -one 3.84 (d, 7= 2.8 Hz, 2H), 3.43 (t, 7 = 6.0 Hz, 2H), 2.82 - 2.80 (m, 2H); MS (ESI+) m/z 376.2 (M+H)+; 91.6% purity, RT 1.6 min (Method Ur 10) 143 1H NMR (CD3OD, 400 MHz) 5 7.57 Prepared according .0. - 7.54 (m, 2H), 7.09 (d, 7= 8.0 Hz, to the method for H 1H), 7.06 - 7.02 (m, 2H), 6.82 (s, 121 starting from 4- HN 1H), 6.74 (d, 7= 6.8 Hz, 1H), 5.79 - fluoroaniline.
/V-(4-fluorophenyl)(3- 5.78 (m, 1H), 3.83 (s, 3H), 3.80 (t, 7 methoxy(l,2,3,6- = 2.4 Hz, 2H), 3.40 (t, 7 = 6.0 Hz, tetrahydropyridin 2H), 2.77 - 2.73 (m, 2H), 2.49 - 2.47 nyl)cyclopropane (m, 1H), 2.07 - 2.05 (m, 1H), 1.62 - carboxamide trifluoroacetic acid 1.59 (m, 1H), 1.39- 1.38 (m, 1H); salt MS (ESI+) m/z 367.1 (M+H)+; 97.6% purity, RT 2.47 min (Method 144 1H NMR , 400 MHz) 5 8.66 0 Prepared according N (s, 1H), 7.79 (d, 7= 8.0 Hz, 1H), to the method for H ^ 7.52 - 7.49 (m, 2H), 7.39 (t, 7= 7.6 121 starting from 2- N.v /7 HN Hz, 1H), 7.09 (d, 7= 7.6 Hz, 1H), (3-methyl-lH- 2-(3-methoxy( 6- 6.79 (s, 1H), 6.72 (d, 7= 8.0 Hz, 1,2,4-triazol-ltetrahydropyridinyl )phenyl)- 1H), 5.78 - 5.77 (m, 1H), 3.82 (s, yl) aniline /V-(2-(3-methyl-1H-1,2,4-triazol- 3H), 3.80 (d, 7= 2.0 Hz, 2H), 3.40 1- (t, 7= 6.0 Hz, 2H), 2.75 (d, 7= 2.0 yl)phenyl)cyclopropanecarboxa Hz, 2H), 2.40 (s, 3H), 2.37 - 2.35 mide trifluoroacetic acid salt (m, 1H), 2.02 - 2.00 (m, 1H), 1.53 - 1.50 (m, 1H), 1.36- 1.29 (m, 1H); MS (ESI+) m/z 430.2 (M+H)+; 98.1% purity, RT 2.33 min (Method 145 1H NMR (CD3OD, 400 MHz) 5 7.93 0 Prepared according N (d, 7 = 8.4 Hz, 1H), 7.16 - 7.10 (m, to the method for F 4H), 6.83 (s, 1H), 6.76 (d, 7 = 7.6 121 starting from 2- HN. Hz, 1H), 5.80 (s, 1H), 3.84 (s, 3H), fluoroaniline /V-(2-fluorophenyl)(3- 3.81 (d, 7 =2.4 Hz, 2H), 3.40 (t, 7 = y(l,2,3,6- 6.0 Hz, 2H), 2.76 (d, 7 = 2.0 Hz, tetrahydropyridin 2H), 2.53 - 2.51 (m, 1H), 2. 62 - yl)phenyl)cyclopropane 2.25 (m, 1H), 1.63 - 1.60 (m, 1H), carboxamide trifluoroacetic acid 1.40 - 1.38 (m, 1H); MS (ESI+) m/z 367.2 (M+H)+; 97.8% purity, RT 2.44 min (Method 11) 146 o iH NMR (CD3OD, 400 MHz) 5 8.33 Prepared according N (d, J= 8.4 Hz, 1H), 7.73 (d, /= 7.6 to the method for Hz, 1H), 7.58 (d, J = 8.0 Hz, 1H), 121 starting from HN. 7.36 (d, /= 7.6 Hz, 1H), 7.10 (d, J = lH-indazolol (3 -hydroxy-1 H-indazol-1 -yl) (2- 8.0 Hz, 1H), 6.87 (s, 1H), 6.79 (d, J (3-methoxy( 1,2,3,6- = 7.6 Hz, 1H), 5.80 - 5.79 (m, 1H), tetrahydropyridinyl)phenyl) 3.92 (s, 3H), 3.83 - 3.81 (m, 2H), cyclopropyl)methanone 3.40 (t, J = 6.0 Hz, 2H), 3.31 (s, oroacetic acid salt 1H), 2.85 - 2.70 (m 2H), 2.68 - 2.66 (m, 1H), 1.82 - 1.80 (m, 1H), 1.59 - 1.58 (m, 1H); MS (ESI+) m/z 390.1 (M+H)+; 96.8% , RT 2.52 min (Method 11) (£)-/V-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147) oO^°' a) ethyl (E)(3-methoxy(oxetanylmethoxy)phenyl)acrylate o o .0. .0.
HO" £T0' To a stirred solution of ethyl (T)(4-hydroxymcthoxyphcnyl(acrylate (1.0 g, 4.5 mmol, 1.0 equiv.) in dry A/.iV-dimethylformamidc (10 mL) under a nitrogen atmosphere at 0°C was added portion-wise sodium e (24 mg, 6.76 mmol, 60 % in mineral oil. 1.5 equiv.).
After ng for 15 minutes in the cold the mixture was treated with a solution of oxetan ylmethyl methanesulfonate (0.90 g, 5.41 mmol, 1.2 equiv.) in di methyl formamidc (5 mL).
The mixture was allowed to warm to room temperature and after 1 hour the reaction was quenched by addition of water (30 mL) and was then extracted with ethyl acetate (150 mL). The c layer was washed with water (7 x 30 mL) and brine (30 mL) and concentrated to dryness under vacuum to give a yellow oil. The crude product was purified by chromatography on silica gel (Interchim 80g column, eluting with 30 - 60% ethyl acetate/isohexane) to afford the title compound as a colourless solid (0.93g, 73%); ‘H NMR (400 MHz, CDCI3): 5 7.64 (s, 1H), 7.60 (s, 1H), 7.11 - 7.05 (m, 1H), 6.90 (d, /= 8.1 Hz, 1H), 6.34 (d, /= 8.1 Hz, 1H), 4.90 (dd, /= 6.3, J = 7.6 Hz, 2H), 4.55 (q, /= 6.1 Hz, 2H), 4.31 - 4.23 (m, 4H), 3.88 (s, 3H), 3.55 - 3.45 (m, 1H), 1.34 (t, 7 = 7.2 Hz, 3H). b) (E)(3-methoxy(oxetanylmethoxy)phenyl)acrylic acid o o .0. .0.
CTa £T0' A stirred mixture of ethyl (£’)(3-methoxy(oxetanylmethoxy)phenyl)acrylate (250 mg, 0.88 mmol, 1.0 ) and lithium hydroxide monohydrate (74 mg, 1.77 mmol, 2.0 equiv.) in 30% aqueous dioxane (13 mL) was heated to 50°C for 2 hours. The e was concentrated in vacuo and then diluted with water (5 mL) and acidified with 2N hydrochloric acid. The precipitate was filtered, washed with water and dried under vacuum to afford the title compound as a colourless solid (190 mg, 81%); ‘H NMR (400 MHz, DMSO): 8 7.56 (d, J = 16.2 Hz, 1H,), 7.37 (d,/= 1.8 Hz, 1H), 7.26 (dd, / = 8.3 Hz,/= 1.8 Hz, 1H), 7.08 (d,/= 8.3 Hz, 1H), 6.52 (d, /= 16.2 Hz, 1H), 4.76 (dd,/= 7.8 Hz,/= 6.1, Hz, 2H), 4.46 (dd,/= 6.1 Hz, / = 6.1 Hz, 2H), 4.29 (d, /= 6.8 Hz, 2H), 3.86 (3H, s), 3.49 - 3.43 (1H, m). c) (E)-N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide .0. .0.
'OH lXjl, CT0' H To a solution of (L)(3-mcthoxy(oxctanylmcthoxy)phcnyl(acrylic acid (60 mg, 0.227 mmol, 1 equiv.) in MiV-dimethylformamidc (2 mL) was added diisopropylethylamine (0.12 mL, 0.682 mmol 3 equiv.) ed by HATU (104 mg, 0.273 mmol, 1.2 equiv.) and 3- chloroaniline (29 mg, 0.227 mmol, 1 equiv.) and the mixture d overnight at room temperature. The product was purified by preparative HPLC and was obtained as an off-white solid (72 mg, 85%); lU NMR (400 MHz, CDCI3): 5 7.73 (m, 2H), 7.67 (s, 1H), 7.46 (dd, /= 8.1 Hz, /= 1.3 Hz, 1H), 7.37 (s, 1H), 7.14 - 7.09 (m, 2H), 7.05 (d, /= 1.8 Hz, 1H), 6.91 (d, /= 8.3 Hz, 1H), 6.43 (d, / = 16.2 Hz, 1H), 4.91 (dd, / = 7.7 Hz, / = 6.4 Hz, 2H), 4.56 (dd, / = 5.9 Hz, / = 5.9 Hz, 2H), 4.30 (d, / = 7.1 Hz, 2H), 3.88 (s, 3H), 3.54 - 3.47 (m, 1H); MS (ESI+) m/z 374/376 (M+H)+; 99.3 % purity, RT 3.32 min (Method 2).
/V-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-lcarboxamide (148) .0. lXXc1 o/r"0' H a) ethyl 2-(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-l-carboxylate o o .0. .0.
£Ta oO^°' A stirred solution of trimethylsulfoxonium iodide (904 mg, 4.11 mmol, 3.0 equiv.) in dimethylsulfoxide (7 mL) was treated with sodium hydride (192 mg, 4.79 mmol, 60 % in mineral oil, 3.5 equiv.). After 1 hour the resultant solution was added ise to a solution of ethyl (£’)(3-methoxy(oxetanylmethoxy)phenyl)acrylate (292 mg, 1.36 mmol, 1 equiv.) m dimethylsulfoxide (7 mL). The mixture was then heated to 80 °C for 18 hours. The cooled e was poured into saturated um chloride solution (50 mL) and extracted with ethyl e (3 x 30 mL). The combined extracts were washed with brine, dried and concentrated to dryness under . The crude product was purified by chromatography on silica gel (Interchim 40g column, eluting with 30 - 60% ethyl acetate/isohexane) to afford the title compound as a colourless oil (203 mg, 48%). ‘H NMR (400 MHz, CDCI3) 8 6.83 (d, 7=8.1 Hz, 1H), 6.67 - 6.61 (m, 2H), 4.88 (dd, 7 = 7.6 Hz, 7= 6.3 Hz, 2H), 4.54 (dd,7=6.1 Hz, 7=6.1 Hz, 2H), 4.24 (d, 7 = 7.1 Hz, 2H), 4.21 - 4.14 (m, 2H), 3.84 (s, 3H), 3.50 - 3.41 (m, 1H), 2.48 (ddd, 7=9.1 Hz, 7 = 6.6 Hz, 7 = 4.0 Hz, 1H), 1.87 - 1.82 (m, 1H), 1.59 - 1.50 (m, 1H), 1.30- 1.25 (m, 4H). b) 2-(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-l-carboxylic acid o o .0. .0.
‘O' ‘OH CTa CTa The title compound was prepared in a similar manner to (£’)(3-methoxy(oxetan- 3-ylmethoxy)phenyl)acrylic acid from ethyl 2-(3-methoxy(oxetan ylmethoxy)phenyl)cyclopropane-l-carboxylate and lithium hydroxide monohydrate and was isolated as a colourless solid (171 mg, 79%); ‘H NMR (400 MHz, CDCI3): 5 6.83 (d, 7= 8.1 Hz, 1H), 6.68 - 6.62 (m, 2H), 4.88 (dd, 7 = 7.6 Hz, 7= 6.3 Hz, 2H), 4.54 (dd, 7= 6.1 Hz, 7= 6.1 Hz, 2H), 4.24 (d, 7 = 7.1 Hz, 2H), 3.84 (s, 3H), 3.51 - 3.42 (m, 1H), 2.57 (ddd, 7= 9.2 Hz, 7= 6.6 Hz, 7 = 4.0 Hz, 1H), 1.88 - 1.82 (m, 1H), 1.66 - 1.59 (m, 1H), 1.36 (ddd, 7= 8.3 Hz 7= 6.7 Hz, 7 = 4.7 Hz, 1H). c) N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropane-l- carboxamide .o. o 'OH MX ocr"0' H The title compound was prepared using a similar method to (T)-A/-(3-chlorophcnyl) (3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147) using 2-(3-methoxy(oxetan ylmethoxy)phenyl) cyclopropanecarboxylic acid and 3-chloroaniline and was obtained as an off-white solid (70%); ‘H NMR (400 MHz, CDC13) 5 7.67 (s, 1H), 7.52 - 7.49 (m, 1H), 7.35 (d, 7= 7.8 Hz, 1H), 7.23 (dd, /= 8.1 Hz, /= 8.1 Hz, 1H), 7.08 (d, / = 7.8 Hz, 1H), 6.86 - 6.82 (m, 1H), 6.67 - 6.63 (m, 2H), 4.90 - 4.84 (m, 2H), 4.55 - 4.50 (m, 2H), 4.25 (d, / = 7.1 Hz, 2H), 3.80 (s, 3H), 3.49 - 3.40 (m, 1H), 2.55 (ddd, /= 9.1 Hz, /= 6.4 Hz, /= 4.0 Hz, 1H), 1.74 - 1.64 (m, 2H), 1.34 (ddd, / = 7.8 Hz, /= 6.6. Hz, / = 4.4 Hz, 1H). MS (ESI+) m/z 388/390 (M+H)+; 97.2% purity, RT 3.39 min (Method 2).
/V-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazol yl)methoxy)phenyl)cyclopropane-l-carboxamide (149) "Xo vO"1 a) 4-methoxy((l-methyl-lH-pyrazolyl)methoxy)benzaldehyde x \ \ Xo OH XT’ ] A stirred solution of (1-methyl-17/-pyrazolyl)methanol (0.74 g, 6.58 mmol, 1 ) in tetrahydrofuran (30 mL) was treated with isovanillin (1.00 g, 6.58 mmol, 1 ) and triphenylphosphine (2.10 g, 7.89 mmol, 1.2 equiv.). The mixture was cooled to 0°C and diisopropyl azodicarboxylate (1.55 mL, 7.89 mmol, 1.2 ) was added drop-wise. The mixture was then allowed to warm to room temperature and was stirred overnight. The mixture was concentrated to dryness under vacuum and the residue purified by chromatography on silica gel chim 80 g column, eluting with 50 - 80% ethyl acetate/isohexane) to afford the title compound as a pale yellow oil (1.37 g, 85%) which was used without further purification; ^ NMR (400 MHz, CDCI3): 5 9.85 (s, 1H), 7.70 - 7.64 (m, 2H), 7.58 - 7.44 (m, 3H), 5.08 (s, 2H), 3.94 (s, 3H), 3.89 (s, 3H). b) ethyl (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylate \ \ To a stirred suspension of sodium hydride (205 mg, 5.12 mmol, 60 % in mineral oil, 1.5 equiv.) in tetrahydrofuran (10 mL) under a nitrogen here was added drop-wise a solution of triethyl phosphonoacetate (840 mg, 3.76 mmol, 1.1 equiv.) in tetrahydrofuran (5 mL).
After 15 minutes a solution of 4-mcthoxy((l-methyl-1 /7-pyrazolyl)mcthoxy)bcnzaldchydc (840 mg, 3.41 mmol, 1.0 ) in tetrahydrofuran (15 mL) was slowly added and the mixture stirred for a further 4 hours. Water (30 mL) was added and the mixture extracted with ethyl acetate (150 mL). The organic phase was washed the brine, dried and concentrated to dryness under vacuum. The residue was purified by chromatography on silica gel (Interchim 80 g column, eluting with 50 - 80% ethyl acetate/isohexane) to afford the title compound as an offwhite solid (786 mg, 85%) which was used without further purification; ^ NMR (400 MHz, CDCI3) 5 7.61 (d, /= 16.3 Hz, 1H), 7.56 (s, 1H), 7.45 (s, 1H), 7.14 - 7.10 (m, 2H), 6.87 (d, / = 8.4 Hz, 1H), 6.28 (d, /= 16.3 Hz, 1H), 5.05 (s, 2H), 4.26 (q, /= 6.9 Hz, 2H), 3.89 (s, 3H), 3.88 (s, 3H), 1.34 (t, 7 = 7.0 Hz, 3H). c) ethyl 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)cyclopropane-l- carboxylate \ \ 0 "’Xo o ■O' •O' The title compound was ed in a r manner to ethyl 2-(3-methoxy nylmethoxy)phenyl)cyclopropane-l-carboxylate from ethyl (£’)(4-methoxy((lmethyl-lH-pyrazolyl )methoxy)phenyl)acrylate to afford the product as a cream solid (31%); Tl NMR (400 MHz, CDCI3): 5 7.53 (s, 1H), 7.44 (s, 1H), 6.79 (d, / = 8.3 Hz, 1H), 6.71 (d,/ = 2.0 Hz, 1H), 6.67 (dd, /= 8.2 Hz, /= 1.9 Hz, 1H), 4.99 (s, 2H), 4.17 (q, / = 7.2 Hz, 2H), 3.89 (s, 3H), 3.82 (s, 3H), 2.49 - 2.42 (m, 1H), 1.84 - 1.78 (m, 1H), 1.58 - 1.52 (m, 1H), 1.31 - 1.21 (m, d) 2-(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)cyclopropane-l-carboxylic \ \ o o "O' "O' The title compound was prepared in a similar manner to (£’)(3-methoxy(oxetan- 3-ylmethoxy)phenyl)acrylic acid from ethyl 2-(4-mcthoxy((l-methyl-1 /7-pyrazol yl)methoxy)phenyl)cyclopropane-l-carboxylate and lithium hydroxide monohydrate and was isolated as a pale yellow gum (94%); ‘H NMR (400 MHz, DMSO): 5 7.81 (s, 1H), 7.52 (s, 1H), 6.91 - 6.87 (m, 2H), 6.73 (dd, / = 8.3 Hz, / = 2.0 Hz, 1H), 4.96 (s, 2H), 3.87 (s, 3H), 3.74 (s, 3H), 2.41 - 2.34 (m, 1H), 1.83 - 1.77 (m, 1H), 1.45 - 1.29 (m, 2H). e) N-(4-chlorophenyl)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)- cyclopropane-1 -carboxamide \ \ (Method 2) (/?)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide (150) a) (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)acrylic acid \ \ 0 o ‘O' ‘O' The title compound was prepared in a similar manner to (£’)(3-methoxy(oxetan- 3-ylmethoxy)phenyl)acrylic acid from ethyl (£)(4-mcthoxy(( l-methyl-lH-pyrazol yl)methoxy)phenyl)acrylate and lithium hydroxide monohydrate and was obtained as an offwhite solid (92%); ‘H NMR (400 MHz, DMSO) 5 12.25 (s, 1H), 7.84 (s, 1H), 7.61 - 7.47 (m, 3H), 7.26 (d, J=7.6 Hz, 1H), 7.03 (d, J=8.1 Hz, 1H), 6.50 (d, J=15.6 Hz, 1H), 5.04 (s, 2H), 3.88 (s, 3H), 3.82 (s, 3H). b) (E)(4-methoxy((l-methyl-lH-pyrazolyl)methoxy)phenyl)-N-(pyridin yl)acrylamide \ \ Oo. o "OH »x° W "O' "O' The title compound was prepared using a r method to (T)-A/-(3-chlorophcnyl) (3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147) using -(4-methoxy((lmethyl-lH-pyrazolyl )methoxy)phenyl)acrylic acid and 3-aminopyridine and was obtained as an off-white solid (63%); NMR (400 MHz, CDC13) 5 8.64 (d, / = 2.5 Hz, 1H), 8.36 (d, / = 4.8 Hz, 1H), 8.31 (d, /= 8.3 Hz, 1H), 7.70 (d, /= 15.3 Hz, 1H), 7.64 (s, 1H), 7.57 (s, 1H), 7.45 (s, 1H), 7.31 (dd, /= 8.3 Hz, / = 4.8 Hz, 1H), 7.17 - 7.12 (m, 2H), 6.89 (d, /= 8.3 Hz, 1H), 6.40 (d, /= 15.3 Hz, 1H), 5.04 (s, 2H), 3.90 (s, 3H), 3.89 (s, 3H); MS (ESI+) m/z 365 (M+H)+; 94.7% , RT 2.88 min (Method 3).
(E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151) a) ethyl (E)(4-methoxymorpholinophenyl)acrylate o o k^NH ‘O' ‘O' ‘O' o To a stirred e of ethyl (T)(3-bromomcthoxyphcnyl(acrylate (0.150 g, 0.53 mmol, 1.0 equiv.), morpholine (0.06 mL, 0.63 mmol, 1.2 equiv.), RuPhos (0.025 g, 0.05 mmol,. 0.1 ) and sodium te/t-butoxide (0.111 g, 1.16 mmol, 2.2 equiv.) in dry, degassed toluene was added palladium acetate (0.006g, 0.03 mmol, 0.05 equiv.) and the mixture stirred under a nitrogen atmosphere under reflux overnight. The reaction was cooled to room temperature and filtered through a plug of celite which was washed with ethyl acetate. The filtrate was concentrated in vacuo and the e ioned between ethyl acetate and water. The organic phase was washed with water and brine and the solvent removed in vacuo. The residue was purified by silica gel column chromatography (20-40% ethyl acetate in hexane as gradient) to afford the title compound as an amber oil (0.081 g, 52%); ^ NMR (400 MHz, CDCI3) d 7.63 (d, / = 16.7 Hz, 1H), 7.20 (dd, 7=8.3 Hz, / = 2.3 Hz, 1H), 7.10 - 7.09 (m, 1H), 6.86 (d, / = 8.6 Hz, 1H), 6.31 (d, / = 16.2 Hz, 1H), 4.26 (q, 7 = 7.1 Hz, 2H), 3.92- 3.88 (m, 7H), 3.10-3.07 (m, 4H), 1.34 (t, 7= 6.5 Hz, 3H). b) (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide Ex Structure Data Method 152 /°- 0 ‘H NMR (400 MHz, CDC13): 5 8.54 Prepared according (d, 7= 7.8 Hz, 1H), 7.77 (s, 1H), to the method for Cl 7.71 (d, 7= 15.6 Hz, 1H), 7.40 (dd, 147 starting from 2- (£)-/V-(2-chloi'ophcnyl)(3- 7= 8.1 Hz, 7= 1.5 Hz, 1H), 7.34 - aniline methoxy(oxetan 7.28 (m, 1H), 7.15 (dd, 7= 8.3 Hz, 7 ylmethoxy)phenyl)acrylamide = 2.0 Hz Hz, 1H), 7.11 -7.03 (m, 2H), 6.92 (d, 7= 8.3 Hz, 1H), 6.49 (d, 7= 16.2 Hz, 1H), 4.91 (dd, 7 = 7.8 Hz, 7= 6.3 Hz, 2H), 4.56 (dd, 7 = 6.1 Hz, 7= 6.1 Hz, 2H), 4.32 (d, 7 = 7.1 Hz, 2H), 3.92 (s, 3H), 3.55 - 3.47 (m, 1H); MS (ESI+) m/z 374/376 ; 97.9 % purity RT 3.28 min (Method 2)_________ 153 Prepared according .0. W' ‘H NMR (400 MHz, CDC13) 5 7.69 (d, 7= 15.4 Hz, 1H), 7.57 (d, 7= 8.8 to the method for ocr* H Hz, 2H), 7.33 - 7.29 (m, 3H), 7.12 147 starting from 4- (dd, 7= 8.2 Hz, 7= 1.9 Hz, 1H), chloroaniline WO 44620 (£)-/V-(4-chl()i'ophcnyl)(3- 7.06 (d, J = 2.0 Hz, 1H), 6.91 (d, J = methoxy(oxetan 8.3 Hz, 1H), 6.40 (d, / = 15.4 Hz, ylmethoxy)phenyl)acrylamide 1H), 4.91 (dd,7=7.6 Hz,/= 6.3 Hz, 2H), 4.56 (dd, /= 6.1 Hz, 6.1 Hz, 2H), 4.30 (d, /= 7.1 Hz, 2H), 3.88 (s, 3H), 3.54 - 3.46 (m, 1H); MS (ESI+) m/z 374/376 (M+H)+ 99.5 % purity RT 3.31 min (Method 154 ‘H NMR (400 MHz, CDC13) 5 7.48 Prepared according (d, /= 8.1 Hz, 2H), 7.42 (s, 1H), to the method for ocr 7.28 (d, /= 8.8 Hz, 2H), 6.84 (d, / = 148 starting from 4- 8.1 Hz, 1H), 6.66 - 6.63 (m, 2H), chloroaniline /V-(4-chlorophenyl)(3 - 4.90 - 4.85 (m, 2H), 4.56 - 4.50 (m, methoxy(oxetan 2H), 4.24 (d, /= 7.1 Hz, 2H), 3.82 ylmethoxy)phenyl)cyclopropane- (s, 3H), 3.49 - 3.42 (m, 1H), 2.59 - 1-carboxamide 2.52 (m, 1H), 1.74 - 1.64 (m, 2H), 1.37 - 1.31 (m, 1H); MS (ESI+) m/z 388/390 (M+H)+97.8% purity, RT 3.37 min (Method 2)____________ 155 0 1^ ‘H NMR (400 MHz, CDC13) 5 8.42 Prepared ing .0. (d, /= 7.3 Hz, 1H), 7.87 - 7.85 (m, to the method for cr°- Cl 1H), 7.37 (dd, 7=8.1 Hz,/= 1.3 148 starting from 2- N-(2-chlorophenyl) (3 - Hz, 1H), 7.30 - 7.27 (m, 1H), 7.06 - chloroaniline methoxy(oxetan 7.01 (m, 1H), 6.86 (d, /= 8.3 Hz, ylmethoxy)phenyl)cyclopropane- 1H), 6.72 (d, /= 2.0 Hz, 1H), 6.66 1-carboxamide (dd, 7=8.1 Hz,/= 2.0 Hz, 1H), 4.89 (dd, / = 7.6 Hz, /= 6.3 Hz, 2H), 4.54 (dd, /= 6.1 Hz, /= 6.1 Hz, 2H), 4.25 (d, /= 7.1 Hz, 2H), 3.86 (s, 3H), 3.51 -3.43 (m, 1H), 2.60 (ddd, /= 9.0 Hz, /= 6.5 Hz, / = 4.0 Hz, 1H), 1.79 - 1.68 (m, 2H), 1.42 - 1.36 (m, 1H); MS (ESI+) m/z 388/390 (M+H)+ 98.3% purity, RT 3.31 min d 2)___________________ 156 »x= \ W, ‘H NMR (400 MHz, CDC13) 5 8.43 Prepared according - 8.39 (m, 1H), 7.85 (s, 1H), 7.53 (s, to the method for 1H), 7.45 (s, 1H), 7.37 (dd, /= 8.1 149 starting from 3- /V-(3 -chlorophenyl)(4- Hz, /= 1.3 Hz, 1H), 7.30 - 7.23 (m, chloroaniline methoxy((l-methyl-lH- 1H), 7.07 - 7.00 (m, 1H), 6.82 (d, / pyrazol = 8.3 Hz, 1H), 6.77 (d, /= 1.8 Hz, yl)methoxy)phenyl)cyclopropane- 1H), 6.70 (dd, /= 8.2 Hz, /= 1.6 1-carboxamide Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.61 - 2.54 (m, 1H), 1.76 - 1.67 (m, 2H), 1.38 - 1.32 (m, 1H); MS (ESI+) m/z 412/414 (M+H)+; 99.6% purity, RT 3.43 min (Method 2).________________ 157 \ o 1HNMR(400MHz, CDC13): 5 Prepared according »Xo 8.43 - 8.39 (m, 1H), 7.85 (s, 1H), to the method for Cl 7.53 (s, 1H), 7.45 (s, 1H), 7.37 (dd, 149 ng from 2- /V-(2-chlorophenyl)(4- /= 8.1 Hz, /= 1.3 Hz, 1H), 7.29 chloroaniline methoxy((l-methyl-lH- (m, 1H), 7.07 - 7.00 (m, 1H), 6.82 pyrazol (d, /= 8.3 Hz, 1H), 6.77 (d, /= 1.8 hoxy)phenyl)cyclopropane- Hz, 1H), 6.70 (dd, /= 8.2 Hz, J = 1-carboxamide 1.6 Hz, 1H), 5.01 (s, 2H), 3.88 (s, 3H), 3.84 (s, 3H), 2.61 - 2.54 (m, 1H), 1.76 - 1.67 (m, 2H), 1.38 - 1.32 (m, 1H). MS (ESI+) m/z 412/414 (M+H)+; 98.5% purity. RT 3.29 min (Method 2)________________ 158 \ *H NMR (400 MHz, DMSO): 5 "XowX8.bJCL/ Prepared according .70 (s, 1H), 8.34 (s, 1H),7.91 - to the method for d' 7.87 (m, 1H), 7.82 (s, 1H), 7.66 - 149 starting from 3- 2-(4-methoxy(( 1 -methyl-1H- 7.62 (m, 2H), 7.53 (s, 1H), 6.96 (d, (methylsulfonyl)ani pyrazolyl)methoxy)phenyl)-N - J= 2.0 Hz, 1H), 6.92 (d, J= 8.3 Hz, line (3 -(methylsulfonyl)phenyl) 1H), 6.76 (dd, /= 8.5 Hz, /= 1.9 cyclopropane-1 -carboxamide Hz, 1H), 4.97 (d, /= 3.3 Hz, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 3.24 (s, 3H), 2.45 - 2.38 (m, 1H), 2.13 - 2.05 (m, 1H), 1.56 - 1.42 (m, 2H). MS (ESI+) m/z 456 (M+H)+; 98.3% purity. RT 3.03 min (Method 2). 159 \ o ‘H NMR (400 MHz, CDC13) 5 8.53 Prepared according Xo (d, /= 7.8 Hz, 1H), 7.76 (s, 1H), to the method for Cl 7.70 (d, J= 15.8 Hz, 1H), 7.57 (s, 150 starting from 2- (£)-/V-(2-chlorophcnyl)(4- 1H), 7.47 (s, 1H), 7.39 (dd, J= 8.1 aniline methoxy((l-methyl-lH- Hz, /= 1.5 Hz, 1H), 7.34 - 7.28 (m, pyrazol 1H), 7.20 - 7.16 (m, 2H), 7.08 - 7.03 yl)methoxy)phenyl)acrylamide (m, 1H), 6.90 (d, /= 8.1 Hz, 1H), 6.43 (d, J= 15.8 Hz, 1H), 5.07 (s, 2H), 3.90 (s, 3H), 3.90 (s, 3H); MS (ESI+) m/z 398/400 ; 99.1% purity, RT 3.33 min (Method 160 \ va, ‘H NMR (400 MHz, CDC13) 5 7.74 Prepared according (dd, /= 2.1 Hz, /= 2.1 Hz, 1H), to the method for \o 7.68 (d, /= 14.9 Hz, 1H), 7.57 (s, 150 starting from 3- (£)-/V-(3-chlorophcnyl)(4- 1H), 7.49 - 7.44 (m, 3H), 7.29 - 7.23 chloroaniline methoxy((l-methyl-lH- (m, 1H), 7.16 - 7.08 (m, 3H), 6.88 l (d, /= 8.3 Hz, 1H), 6.35 (d, /= 15.4 yl)methoxy)phenyl)acrylamide Hz, 1H), 5.03 (s, 2H), 3.89 (s, 3H), 3.88 (s, 3H); MS (ESI+) m/z 398/400 (M+H)+; 99.5% purity, RT 3.35 min (Method 3)_________ Biological Activity Proline incorporation plus MTS viability assay The compounds of the disclosure were evaluated to determine the effect of inhibitors on collagen biosynthesis in a [14C]-proline incorporation assay and cell ity using a MTS olium reduction assay. In particular, the assay evaluated inhibition of TGF-P induced [14C]- proline incorporation in rat mesangial cells.
Table 1. Reagents and consumables Reagent/Consumable Supplier Cat No. 1097 / IRMC cells FibroTech (Shire) DMEM + Glutamax Invitrogen 31966-021 Foetal Bovine Serum (FBS) Invitrogen 10082-147 Pen-Strep Invitrogen 15140-122 Ascorbic acid phosphate magnesium salt Sigma A8960-5G (APM)_______________________________ Chlorpromazine hydrochloride Sigma C8138-5G TGF-p 1 PreproTech 100-21 1M hydrochloric acid (HC1) Fluka 35328-1L Bovine serum albumin (BSA) Sigma A7906 [14C]-proline Perkin Elmer NEC851250UC MTS Promega G5430 96 well CytoStar-T plates Perkin Elmer RPNQ0163 Adhesive Topseal A-Plus Perkin Elmer 6050185 Day 1 - Plating cells: Seed IRMC cells at 10,000 200pl (= 50,000 cells/ml) in DMEM supplemented with 5% FBS in 96 well CytoStar-T plates; Leave plates 1 hour at room temperature before erring to 37°C/5% CO2 incubator and incubate overnight.
Day 2 - Serum starvation: te off media; Replace with 150pl of 150pM APM made up in DMEM supplemented with 0.1% FBS and 1% Pen-Strep (Starvation media); Return plates to the 37°C/5% CO2 incubator overnight.
Day 3: Compound addition: Add 20 pi of: 10X compound in tion media, 10% DMSO in starvation media to controls and no TGF-P 1 blanks, 100 pM romazine hydrochloride to dead cell blanks, and Reference compound tranilast (ADS ) tested from IpM - 300pM; Return plates to 37°C/5% CO2 incubator and incubate for 4 hours; Add lOpl of: ng/ml TGF-P 1 (final concentration = Ing/ml) to all wells except no TGF- pi blanks, and WO 44620 Starvation media to TGF-pi blanks; Add 20 |il of 1 |jCi/ml [14C]-proline (final concentration = 0.1 ) and 1.5 mM APM (final concentration = 150 pM) made up in starvation media; Return plates to the 37°C/5% CO2 incubator and incubate for 44 hours.
Day 5: r14Cl-proline and MTS assay: Remove plates from incubator and transfer to radioactive work area in ADI in appropriate container; Seal plates with adhesive seals; Place plates in counting cassettes and Count on eta using n_14C protocol; Once plates have finished ng, remove seals and aspirate off media; Add 200 pi of 1:21 dilution of MTS reagent; Return plates to the 37°C/5% CO2 incubator and incubate for further 2 hours; Remove plates from incubator and transfer to radioactive work area in ADI in appropriate container; Seal plates with adhesive seals; Read absorbance at 490nm on Spectramax M5e.
] Final Assay volumes / concentrations (Day 31: 150 pi cells in 150 pM APM made up in starvation media; 20 pi Compound / Controls / Blanks / Dead Cell Blanks in 1% DMSO; 10 pi 1 ng/ml or 0 ng/ml TGF-pi (Blanks); 20 pi 0.1 pCi/ml [14C]-proline / 150 pM APM.
IC50 generation - [14C]-proline incorporation. TGF-pi-induced proline incorporation was determined by subtraction of basal (non-TGF-pi treated cells) CPM from the TGF-pi stimulated cell CPM. % inhibition of the 1% DMSO vehicle stimulated TGF-pi response at each concentration of compound was calculated by the formula: (100-(((test data - blank data)/(control data - blank data))* 100)). IC50 values were generated from the ated log dose-response curve fits using ActivityBase (IDBS).
] CC50 generation - cell viability. The effects of compound on cell viability were quantified by comparison to the 1% DMSO vehicle-treated TGF-pi stimulated cells, which were used as the 100% viability reference. % cell viability at each tration of compound was calculated by the formula: (((test data - blank data)/(control data - blank data))* 100). CC50 values were generated from the associated log dose-response curve fits using ActivityBase (IDBS).
Table 2 provides the assay results of the example compounds of the present disclosure.
Table 2.
IC50 (pM) CC50 (pM) 106 1.579 25.096 9 1.94 25.478 7 1.97 62.54 159 2.427 > 10 143 2.814 7.2 120 3.218 10.799 82 3.419 13.516 87 3.688 12.102 145 3.705 11.741 121 3.792 8.473 126 3.812 > 27.546 102 3.871 11.411 3 3.936 71.142 150 4.075 >31.623 136 4.134 16.263 4 4.317 323.001 88 4.449 12.372 89 4.662 19.784 77 4.689 26.47 141 4.851 13.502 93 5.227 17.24 8 5.335 109.497 139 5.363 9.028 6.038 66.438 40 6.764 >300 115 7.028 45.398 11 7.073 2 81 7.146 24.877 113 7.747 32.642 149 8.353 > 54.772 91 8.376 18.074 105 8.439 79.717 140 8.469 36.121 148 8.475 77.555 85 8.92 108.723 154 8.972 >300 100 9.293 36.959 57 9.366 >76.621 79 9.52 23.378 12 10.203 334.782 14 10.367 48.916 2 10.43 >300 10.55 368.548 1 10.945 >300 138 10.976 50.896 52 11.341 7 6 11.381 >300 128 11.494 24.402 28 11.555 146.496 11.804 37.171 132 11.965 16.564 59 12.121 147.593 71 12.195 116.353 129 12.329 28.878 157 12.644 45.334 45 12.949 307.408 24 12.974 41.361 112 12.984 >300 44 13.224 11.074 26 13.454 189.712 98 13.549 288.628 31 13.855 >300 110 13.871 >300 64 14.211 141.569 114 14.277 82.035 118 14.309 25.477 74 14.679 318.544 84 14.749 >300 107 14.877 > 100 76 14.886 18.084 53 14.962 225.798 72 14.967 >300 137 15.354 30.79 51 15.489 >300 130 15.589 51.799 36 15.84 15.168 22 16.353 240.422 101 16.956 119.375 42 16.965 51.963 66 16.98 >300 122 17.15 234.488 18 17.196 150.629 134 17.475 >300 125 17.633 >300 95 17.637 110.748 156 17.822 > 100 37 18.027 29.157 63 18.184 79.385 65 18.279 151.764 155 18.722 196.232 123 19.333 >300 146 19.577 >300 19 19.665 122.039 60 20.321 100.172 144 20.928 81.022 117 21.354 >300 27 21.443 3 131 21.553 17.713 94 21.653 35.043 90 21.9 >300 16 22.338 107.391 133 23.44 >300 67 23.469 144.286 48 23.861 309.178 54 24.004 >300 109 24.26 >300 80 24.46 > 100 119 24.717 74.751 41 24.845 341.082 86 24.928 >300 21 24.975 >300 25.24 303.574 49 25.264 30.57 29 25.632 >300 158 25.888 68.838 23 26.313 103.647 32 27.356 32.019 75 27.608 >300 103 27.994 264.891 34 28.437 37.258 47 29.103 >300 33 29.249 199.079 111 29.977 >300 160 30.356 >300 78 30.45 404.427 151 31.551 >300 17 31.645 >300 142 31.687 >300 56 32.238 150.03 83 32.469 >300 73 33.076 >300 96 33.626 >300 99 34.747 >300 124 34.752 >300 153 35.395 >300 127 35.415 82.939 13 36.042 96.448 37.416 301.223 152 38.173 >300 38 38.23 236.349 147 39.084 >300 58 39.221 265.689 39.506 >300 108 40.398 >300 104 41.364 280.87 55 44.339 86.083 43 44.556 >300 68 44.861 >300 135 45.273 >300 45.547 >300 97 46.208 >300 46 46.579 186.19 50 47.422 107.475 39 48.256 85.832 69 48.351 691.029 61 48.932 276.157 62 49.012 320.758 92 49.215 108.846 70 49.759 >300 116 60.453 294.25 116 192.65 >300 FT011 16 119 Pharmacokinetic studies Discrete oral pharmacokinetic s were performed for example compounds 116, 107, and 102. 116: 2 mg/kg and 20 mg/kg of 116 were administered as single doses to male Sprague Dawley (SD) rats. 75 mg/kg and 350 mg/kg of 116 were administered daily (5 days) to male e Dawley (SD) rats. Figure 1 shows the time versus concentration profile after administration of the initial dose of all dosing groups. No e compound related effects were observed at any dose level, and little to no increase in plasma concentrations were observed between the 75 and 350 mg/kg/day dosing groups. However, trough concentrations for the 350 mg/kg/day dosing group were lower than ed throughout the 5-day study e 2).
The pharmacokinetic results were compared to the known compound (E)(3-(3- methoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (FT011), which has an IC50 of 17 pM and a CCsoof 119 pM in the assays described above. Figure 3 shows that coverage of IC50 ve to a 200 day regime of (E)(3-(3-methoxy(propyn-l- yloxy)phenyl)acrylamido)benzoic acid (shown as a straight line at 0.10 of the y-axis in Figure 3) was superior for 116 at 75 mg/kg and 350 mg/kg even though it possesses a less potent IC50. 107: 2 mg/kg and 20 mg/kg of 107 were administered as single doses to male Sprague Dawley (SD) rats. 75 mg/kg and 350 mg/kg of 107 were administered daily (5 days) to male Sprague Dawley (SD) rats. Figure 4 shows the time versus concentration profile after administration of the initial dose of all dosing groups. No adverse compound related effects were observed at any dose level, and an increase in plasma concentrations were observed between the 75 and 350 mg/kg/day dosing groups. In addition, trough concentrations for the 75 and 350 mg/kg/day dosing group were tent with dosing amounts throughout the 5-day study {Figure 5).
The pharmacokinetic results were also compared to the known compound (E)(3-(3- methoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (FT011). Figure 6 shows that coverage of IC50 ve to a 200 mg/kg/day regime of (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (shown as a straight line at 0.10 of the y-axis in Figure 6) was or for 107 at 350 mg/kg. 102: 2 mg/kg and 20 mg/kg of 102 were administered as single doses to male Sprague Dawley (SD) rats. 75 mg/kg and 350 mg/kg of 102 were stered daily (5 days) to male Sprague Dawley (SD) rats. Figure 7 shows the time versus concentration profile after administration of the initial dose of all dosing groups. An increase in plasma concentrations were observed between the 75 and 350 mg/kg/day dosing groups. In addition, trough concentrations for the 75 and 350 mg/kg/day dosing group were consistent with dosing amounts throughout the -day study (Figure 8).
The pharmacokinetic s were also ed to the known compound (E)(3-(3- methoxy(propyn-l-yloxy)phenyl)acrylamido)benzoic acid (FT011). Figure 9 shows that coverage of IC50 relative to a 200 mg/kg/day regime of (E)(3-(3-methoxy(propyn-lyloxy )phenyl)acrylamido)benzoic acid (shown as a ht line at 0.10 of the y-axis in Figure 9) was or for 102 at 20 mg/kg, 75 mg/kg and 350 mg/kg.
Equivalents and Scope In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context.
The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The ion includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process.
Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For e, any claim that is dependent on another claim can be modified to include one or more tions found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group , each subgroup of the elements is also disclosed, and any t(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms "comprising" and "containing" are intended to be open and s the inclusion of onal elements or steps.
Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub-range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context y dictates otherwise.
The recitation of a listing of chemical groups in any definition of a variable herein es tions of that le as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other ments or portions thereof. The recitation of an embodiment herein includes that ment as any single embodiment or in combination with any other embodiments or ns thereof.
This application refers to various issued s, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art.
Those d in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the t embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made t departing from the spirit or scope of the present invention, as d in the following claims.

Claims (18)

1. A compound of Formula I: or a ceutically acceptable salt thereof; wherein T is ; X is O; Y is O; Z is a bond; R1 is C2-4 alkynyl; R2 is C1-4 alkyl; R3 is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein R3 is optionally substituted with –NRaRb or alkyl; R4 and R5 are hydrogen; each occurrence of R6 is, independently, F, Cl or Br; G is hydrogen; m is 1 or 2; and each occurrence of Ra and Rb is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, 1-6 alkyl, C(O)C1-6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
2. A compound of Formula I: or a pharmaceutically acceptable salt thereof; wherein T is ; X is O; Y is O; Z is a bond; R1 is C2-4 alkynyl; R2 is C1-4 alkyl; R3 is hydrogen, alkyl, alkynyl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, n R3 is optionally substituted with -NRaRb or alkyl; R4 and R5 are en; G is C(O)R7; R7 is NHR9; m is 0; R9 is tetrazolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, each of which is optionally substituted with up to two alkyl groups; and each occurrence of Ra and Rb is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(O)OC1-6 alkyl, C(O)C1-6 alkyl, or Ra and Rb er with the atoms to which they are attached form a heterocyclyl ring.
3. A nd of Formula I-i: or a pharmaceutically acceptable salt thereof; wherein X is O and Y is NR10; X is NR10 and Y is O; or X is NR10 and Y is NR10; each occurrence of Rg and Rh is, ndently, hydrogen or alkyl, or Rg and Rh together with the carbon atom to which they are attached form a carbonyl; t is 1 or 2; each occurrence of R10 is, independently, hydrogen or C1-4 alkyl optionally substituted with 1-3 independent substituents R8; each occurrence of R8 is, independently, alkyl, alkynyl, hydroxyl, , carboxyl, oxo, aryl, heteroaryl, heterocyclyl, -NRaRb, -S(O)2Rc, or -CO2Rd; and each ence of Ra, Rb, Rc, and Rd is, independently, hydrogen, acyl, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocyclylalkyl, aryl, heteroaryl, heterocyclyl, C(O)OC1-6 alkyl, -6 alkyl, or Ra and Rb together with the atoms to which they are attached form a heterocyclyl ring.
4. The compound according to claim 3, or a ceutically acceptable salt thereof, wherein R10 is methyl .
5. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein R10 is hydrogen .
6. The compound according to claim 3, or a pharmaceutically acceptable salt thereof, wherein: X is O; Y is NR10; and R10 is C1-4 alkyl .
7. The compound according to claim 3, or a pharmaceutically able salt thereof, wherein: X is NR10; Y is O; and R10 is C1-4 alkyl .
8. The compound according to any one of claims 3 to 7, or a pharmaceutically acceptable salt thereof, wherein t is 2.
9. The compound according to any one of claims 3 to 8, or a pharmaceutically acceptable salt f, wherein each occurrence of Rg and Rh is hydrogen.
10. The compound according to any one of claims 3 to 8, or a pharmaceutically acceptable salt f, wherein t is 2; and wherein one occurrence of Rg and Rh is hydrogen, and the other occurrence of Rg and Rh is that Rg and Rh together with the carbon atom to which they are attached form a carbonyl.
11. A compound ed from the group consisting of: (E)-N-(2-fluorophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (1); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(5-methyl-1H-1,2,4-triazol yl)phenyl)acrylamide (2); (E)-N-(2-chlorophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (3); (E)-N-(2-bromophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (4); (E)(3-methoxy(propynyloxy)phenyl)-N-(o-tolyl)acrylamide (5); (E)-N-(2-cyanophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (6); (E)-N-(3,4-dichlorophenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (7); (E)-N-(2-(2H-tetrazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (16); (E)-N-(2-(1,2,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (17); (3-methoxy(propynyloxy)phenyl)-N-(2-(5-methyl-1,2,4-oxadiazolyl)phenyl)- acrylamide (18); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(5-oxo-4,5-dihydro-1,2,4-oxadiazol yl)phenyl)acrylamide (19); (E)-N-(2-(1,2,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (20); (E)-N-(2-(1,3,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (21); (3-methoxy(propynyloxy)phenyl)-N-(2-(1-methyl-1H-pyrazolyl)phenyl)- acrylamide (22); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazol yl)phenyl)acryl-amide (23); (E)-N-(2-(1H-pyrazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (24); (E)-N-(2-(1H-imidazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (25); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(1-methyl-1H-imidazol yl)phenyl)acrylamide (26); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(methylsulfonyl)benzamide (27); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(3-methyl-1,2,4-oxadiazol yl)phenyl)acryl-amide (28); (E)(3-methoxy(propynyloxy)phenyl)-N-(2-(5-methyl-1,3,4-oxadiazolyl)phenyl)- acrylamide (29); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2H-tetrazolyl)benzamide (31); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(1-methylpiperidin yl)benzamide (36); (3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(oxetanyl)benzamide (38); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridinyl)benzamide (44); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(1-methyl-1H-pyrazol yl)benzamide (47); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(1-methyl-1H-pyrazol yl)benzamide (48); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(piperidinyl)benzamide (49); (E)(3-(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)acrylamido)benzoic acid (51); (E)-N-(3-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxypropynoxyphenyl ]propenamide (76); ((E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxy(propyn yloxy)phenyl)acrylamide (77); (E)(3-(2-(2-(dimethylamino)ethoxy)methoxy(propynyloxy)phenyl)acrylamido)- c acid (78); (E)-N-(2-cyanophenyl)[3-methoxy(1-methylazetidinyl)oxypropynoxyphenyl ]propenamide (79); 2-[[(E)(3-methoxypropynoxypyrrolidinyloxyphenyl)propenoyl]amino]benzoic acid (80); (E)-N-(2-cyanophenyl)[3-methoxy(1-methylpyrrolidinyl)oxypropynoxyphenyl ]propenamide (81); (E)-N-(2-cyanophenyl)(3-methoxypropynoxypyrrolidinyloxy-phenyl)prop enamide (82); 2-[[(E)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]propenoyl]amino]benzoic acid (83); 2-[[(E)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enoyl]amino]benzoic acid (84); (E)-N-(2-cyanophenyl)[3-methoxy(2-morpholinoethoxy)propynoxy-phenyl]prop enamide (85); 2-[[(E)[2-[3-(dimethylamino)propoxy]methoxypropynoxy-phenyl]prop enoyl]amino]benzoic acid (86); (E)-N-(2-cyanophenyl)[2-[3-(dimethylamino)propoxy]methoxypropynoxyphenyl 2-enamide (87); (E)-N-(2-cyanophenyl)[3-methoxy(4-piperidyloxy)propynoxy-phenyl]prop enamide (88); (E)-N-(2-cyanophenyl)[3-methoxy[(1-methylpiperidyl)oxy]propynoxyphenyl ]propenamide (89); 2-[[(E)[4-(cyclopropylmethoxy)[2-(dimethylamino)ethoxy]methoxy-phenyl]prop enoyl]amino]benzoic acid (90); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (91); (E)-N-(2-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (92); (E)-N-(3-cyanophenyl)(2-(2-(dimethylamino)ethoxy)methoxyphenyl)acrylamide (93); (E)-N-(2-cyanophenyl)[2-[2-(dimethylamino)ethoxy]methoxy-phenyl]propenamide (94); (E)(3-(3,4-dimethoxy(propynyloxy)phenyl)acrylamido)benzoic acid (95); (E)(3-(3,4-dimethoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (96); (E)(3-(3-methoxy(4-methylpiperazinyl)phenyl)acrylamido)benzoic acid (97); (E)(3-(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (98); (3-(3-methoxy(1-methyl-1,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (99); (E)(3-(4-methoxymorpholinophenyl)acrylamido)benzoic acid (101); (E)(3-(3-methoxymorpholinophenyl)acrylamido)benzoic acid (103); (E)(3-(4-methoxy(1-methyl-1,2,3,6-tetrahydropyridinyl)phenyl)acrylamido)benzoic acid (104); 2-[[(E)(4-methyl-2,3-dihydro-1,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)-N-(2-(1,2,4-oxadiazolyl)phenyl)(3-methoxy(propynyloxy)phenyl)acrylamide (108); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (110); (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (111); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (112); (3-ethyl(propynyloxy)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazolyl)phenyl)- acrylamide (114); (E)(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (116); (E)chloro(3-(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamido)benzoic acid (117); (E)-N-(4-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (120); N-(4-cyanophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (121); 2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)cyclopropane carboxamide (122); (E)(3-ethyl(propynyloxy)phenyl)-N-(2-fluorophenyl)acrylamide (123); (E)-N-(4-cyanophenyl)(3-ethyl(propynyloxy)phenyl)acrylamide (124); (E)(3-ethyl(propynyloxy)phenyl)-N-(4-fluorophenyl)acrylamide (125); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(2-fluorophenyl)acrylamide (127); (E)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)-N-(4-fluorophenyl)acrylamide (128); (E)-N-(4-cyanophenyl)(2-(2-(dimethylamino)ethoxy)-3,4-dimethoxyphenyl)acrylamide (129); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (130); (E)-N-(4-cyanophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)acrylamide (131); (E)-N-(4-fluorophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)acrylamide (132); N-(4-fluorophenyl)(3-methoxy(propynyloxy)phenyl)cyclopropanecarboxamide (133); N-(4-cyanophenyl)(3-methoxy(propynyloxy)phenyl)cyclopropanecarboxamide (135); N-(4-fluorophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)cyclopropane amide (136); N-(4-cyanophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (137); N-(2-fluorophenyl)(3-methoxy((1-methylpyrrolidinyl)oxy)phenyl)cyclopropane carboxamide (138); (E)-N-(4-cyanophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (139); (E)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazol yl)phenyl)acrylamide (140); (E)-N-(2-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)acrylamide (141); N-(4-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (143); 2-(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)-N-(2-(3-methyl-1H-1,2,4-triazol yl)phenyl)cyclopropanecarboxamide (144); N-(2-fluorophenyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)cyclopropane carboxamide (145); (3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (147); N-(3-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropanecarboxamide (148); N-(4-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)cyclopropane- 1-carboxamide (149); (E)-N-(3-chlorophenyl)(4-methoxymorpholinophenyl)acrylamide (151); (E)-N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (152); (E)-N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)acrylamide (153); N-(4-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropanecarboxamide (154); N-(2-chlorophenyl)(3-methoxy(oxetanylmethoxy)phenyl)cyclopropanecarboxamide (155); N-(3-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)cyclopropane- 1-carboxamide (156); N-(2-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)cyclopropane- 1-carboxamide (157); 2-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)-N-(3-(methylsulfonyl)phenyl) cyclopropanecarboxamide (158); (E)-N-(2-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazol yl)methoxy)phenyl)acrylamide (159); (3-chlorophenyl)(4-methoxy((1-methyl-1H-pyrazol yl)methoxy)phenyl)acrylamide (160); (E)(3-methoxy(propynyloxy)phenyl)-N-phenylacrylamide (8); methyl (E)(3-(3-methoxy(propynyloxy)phenyl)acryloyl)-1,2,3,4-tetrahydroquinoline- 4-carboxylate (9) (E)(3,4-dihydroquinolin-1(2H)-yl)(3-methoxy(propynyloxy)phenyl)propen one (10); (E)(3,4-dihydroquinoxalin-1(2H)-yl)(3-methoxy(propynyloxy)phenyl)propen- 1-one (11); (E)(2,3-dihydro-4H-benzo[b][1,4]oxazinyl)(3-methoxy(propyn yloxy)phenyl)propenone (12); (E)-N-((trans)aminocyclohexyl)(3-methoxy(propynyloxy)phenyl)acrylamide (13); (E)(4-hydroxy-3,4-dihydroquinolin-1(2H)-yl)(3-methoxy(propyn yloxy)phenyl)propenone (14); (E)(3-hydroxy-1H-indazolyl)(3-methoxy(propynyloxy)phenyl)propenone (15); (E)-N-(2-(dimethylamino)ethyl)(3-(3-methoxy(propyn 1yloxy) phenyl) acrylamido) benzamide (30); (3-(dimethylamino)propyl)(3-(3-methoxy(propynyloxy)phenyl)acrylamido) benzamide (32); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-methoxyethyl)benzamide (33); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-(4-methylpiperazin yl)ethyl)benzamide (34); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-morpholino benzamide (35); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-((1-methylpiperidin yl)methyl)benzamide (37); (3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-((tetrahydrofuran yl)methyl)benzamide (39); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-((1-methyl-1H-imidazol yl)methyl)benzamide (40); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (41); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (42); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridin ylmethyl)benzamide (43); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(pyridin yl)benzamide (45); (E)(3-(3-methoxy(propynyloxy)phenyl)acrylamido)-N-(2-(pyridin yl)ethyl)benzamide (46); (E)(3-(3-methoxy(piperidinylmethoxy)phenyl)acrylamido)benzoic acid (50); (E)(3-(4-((3,5-dimethylisoxazolyl)methoxy)methoxyphenyl)acrylamido)benzoic acid (52); (E)(3-(3-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (53); (E)(3-(3-methoxy(oxetanylmethoxy)phenyl)acrylamido)benzoic acid (54); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (56); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (57); (E)(3-(3-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (59); (E)(3-(3-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (60); (E)(3-(4-methoxy(2-methoxyethoxy)phenyl)acrylamido)benzoic acid (61); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (62); (E)(3-(4-methoxy(pyridinylmethoxy)phenyl)acrylamido)benzoic acid (63); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (64); (E)(3-(4-methoxy(2-(pyridinyl)ethoxy)phenyl)acrylamido)benzoic acid (65); (E)(3-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (67); (E)(3-(3-methoxy((4-methylpiperazinyl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); (E)(3-(4-methoxy(((1-methylpiperidinyl)oxy)methyl)phenyl)acrylamido)benzoic acid (E)(3-(4-methoxy((propynyloxy)methyl)phenyl)acrylamido)benzoic acid (71); (E)(3-(3-methoxy((propynyloxy)methyl)phenyl)acrylamido)benzoic acid (72); (E)(3-(4-methoxy(methoxymethyl)phenyl)acrylamido)benzoic acid (73); (E)(3-(4-methoxy((propynylamino)methyl)phenyl)acrylamido)benzoic acid (74); (E)(3-(3-methoxy((propynylamino)methyl)phenyl)acrylamido)benzoic acid (75); (E)(3-(4-ethylmethoxyphenyl)acrylamido)benzoic acid (100); 2-[[(E)[4-(cyclopropylmethyl)methoxyphenyl]propenoyl]amino]benzoic acid (102); (E)(3-(3-ethylmethoxyphenyl)acrylamido)benzoic acid (105); (E)(3-(3-(cyclopropylmethyl)methoxyphenyl)acrylamido)benzoic acid (106); (E)(2H-benzo[b][1,4]oxazin-4(3H)-yl)(3-ethyl(propynyloxy)phenyl)propen one (113); (E)(2H-benzo[b][1,4]oxazin-4(3H)-yl)(2-(2-(dimethylamino)ethoxy)-3,4- oxyphenyl)-propenone (115); (E)(2H-benzo[b][1,4]oxazin-4(3H)-yl)(3-methoxy((1-methylpyrrolidin yl)oxy)phenyl)propenone (118); (2H-benzo[b][1,4]oxazin-4(3H)-yl)(2-(3-methoxy(propynyloxy) phenyl) cyclopropyl) methanone (119); (E)(3-ethyl(propynyloxy)phenyl)(3-hydroxy-1H-indazolyl)propenone (126); (3-hydroxy-1H-indazolyl)(2-(3-methoxy(propynyloxy)phenyl)cyclopropyl) methanone (134); (E)(3-hydroxy-1H-indazolyl)(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl)prop- 2-enone (142); (3-hydroxy-1H-indazolyl)(2-(3-methoxy(1,2,3,6-tetrahydropyridinyl)phenyl) cyclopropyl)methanone (146); (E)(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)-N-(pyridinyl)acrylamide (150); and pharmaceutically acceptable salts thereof .
12. The compound ing to claim 11, wherein the compound is ed from the group consisting of: (E)(3-(4-methoxy((1-methyl-1H-pyrazolyl)methoxy)phenyl)acrylamido)benzoic acid (66); (E)(3-(3-methoxy((4-methylpiperazinyl)methyl)phenyl)acrylamido)benzoic acid (68); (E)(3-(3-methoxy(morpholinomethyl)phenyl)acrylamido)benzoic acid (69); 2-[[(E)(4-methyl-2,3-dihydro-1,4-benzoxazinyl)propenoyl]amino]benzoic acid (107); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (109); (E)(3-(4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (110); (E)(3-(3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (111); (E)(3-(4-methyloxo-3,4-dihydro-2H-benzo[b][1,4]oxazinyl)acrylamido)benzoic acid (112); and ceutically acceptable salts thereof.
13. A ceutical composition comprising a nd according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
14. Use of a compound according to any one of claims 1 to 12, or a ceutically acceptable salt thereof, or the pharmaceutical composition according to claim 13, in the manufacture of a medicament for treating a disease or ion ated with fibrosis in a t in need thereof.
15. The use according to claim 14, wherein the disease or condition is selected from the group consisting of fibrotic skin disorders, lung disease, heart disease, kidney disease, and cirrhosis of the liver.
16. The use according to claim 15, wherein the disease or condition is kidney disease.
17. The use according to claim 16, wherein the kidney disease is ssive kidney disease, glomerulonephritis, diabetic kidney disease, diabetic nephropathy, systemic lupus, primary glomerulonephritis, membranous nephropathy, focal segmental glomerulosclerosis, membranoproliferative glomerulonephritis, diffuse proliferative glomerulonephritis, membranous focal segmental glomerulosclerosis, secondary glomerulonephritis, or ischemic nephropathy.
18. The method of claim 16, wherein the kidney disease is focal tal glomerulosclerosis. Single and multi-day oral dosing of 11S to male SD rats at 2,20,75 and 350 mg/kg/day 100000 LfTT-rr J? 10000 i 1000 o 100 E —0—2 mg/kg/day 10 —□—20 mg/kg/day 75 mg/kg/day ■m—350 mg/kg/day T T T T 0 K 'J 10 15 20 25 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) Plasma concentrations of 116 following daily 75 or 350 mg/kg/day oral dosing to SD rats 100000 l 10000 1 1000 o 100 ~-~o-~~75 mg/kg/day —□—350 mg/kg/day 0 20 40 60 80 100 120 140 Time post first dose ) FIG, 2 SUBSTITUTE SHEET (RULE 26) 100.00 —o--—2 day -o- 20 mg/kg/day —&—75 mg/kg/day —350 mg/kg/day FT011 200 mg/kg/day 10.00 G* 1.00 0.01 T T T T 1 0 5 10 15 20 25 SUBSTITUTE SHEET (RULE 26) Single and multi-day oral dosing of 107 to male SD rats at 2,20,75 and 350 mg/kg/day i 1000 o 100 2 mg/kg/day m -~h>~-2Q mg/kg/day O-, 10 -*—75 day —h—350 mg/kg/day T T 1 or 10 15 20 25 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) Plasma trations of 107 following daily 75 or 350 mg/kg/day oral dosing to SD rats I 1000 Ou 10 mg/kg/day —□—350 mg/kg/day 20 40 60 80 100 120 140 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) Percentage IC5Q coverage following daily oral dosing with 107 at 2,20,75 and 350 mg/kg/day 100.00 2 mg/kg/day —□— 20 mg/kg/day —&—75 day 10.00 3> 1.00 0,10 iOK X Mv. X 0,01 T T T r 5 10 15 20 25 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) 100000 E 10000 i 1000 100 ■■.......o E day 10"—I —□—20 mg/kg/day —&r—7h mg/kg/day 350 mg/kg/day T T T 1 0 or 10 15 20 25 SUBSTITUTE SHEET (RULE 26) Plasma concentrations of 102 following daily 75 or 350 mg/kg/day oral dosing to SD rats 'vSSS « 1000I m -0—75 mg/kg/day —o—350 day 100 T T T T T T 1 0 20 40 60 80 100 120 140 Time post dose (hours) SUBSTITUTE SHEET (RULE 26) WO 44620 100,00 -V--— g, 1,00-33=Q-— —©—2mg/kg/day 20 mg/kg/day —^— 75 mg/kg/day -~h*--~350 mg/kg/day ----- FT011 200 mg/kg/day 0 5 10 15 20 25 SUBSTITUTE SHEET (RULE 26)
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